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1
Thach, Trung Thanh, Donghyuk Shin, Seungsu Han, and Sangho Lee. "New conformations of linear polyubiquitin chains from crystallographic and solution-scattering studies expand the conformational space of polyubiquitin." Acta Crystallographica Section D Structural Biology 72, no. 4 (March 30, 2016): 524–35. http://dx.doi.org/10.1107/s2059798316001510.
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The conformational flexibility of linkage-specific polyubiquitin chains enables ubiquitylated proteins and their receptors to be involved in a variety of cellular processes. Linear or Met1-linked polyubiquitin chains, associated with nondegradational cellular signalling pathways, have been known to adopt multiple conformations from compact to extended conformations. However, the extent of such conformational flexibility remains open. Here, the crystal structure of linear Ub2was determined in a more compact conformation than that of the previously known structure (PDB entry 3axc). The two structures differ significantly from each other, as shown by an r.m.s.d. between Cαatoms of 3.1 Å. The compactness of the linear Ub2structure in comparison with PDB entry 3axc is supported by smaller values of the radius of gyration (Rg; 18versus18.9 Å) and the maximum interatomic distance (Dmax; 55.5versus57.8 Å). Extra intramolecular hydrogen bonds formed among polar residues between the distal and proximal ubiquitin moieties seem to contribute to stabilization of the compact conformation of linear Ub2. An ensemble of three semi-extended and extended conformations of linear Ub2was also observed by small-angle X-ray scattering (SAXS) analysis in solution. In addition, the conformational heterogeneity in linear polyubiquitin chains is clearly manifested by SAXS analyses of linear Ub3and Ub4: at least three distinct solution conformations are observed in each chain, with the linear Ub3conformations being compact. The results expand the extent of conformational space of linear polyubiquitin chains and suggest that changes in the conformational ensemble may be pivotal in mediating multiple signalling pathways.
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Pavelčík, František, and Eva Luptáková. "The empirical conformational surface of the co(ethylenediamine) ring." Collection of Czechoslovak Chemical Communications 55, no. 6 (1990): 1427–34. http://dx.doi.org/10.1135/cccc19901427.
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The conformational surface of the Co(en) chelate ring was studied by the method of structural correlation. The reduction of dimensionality of the conformation problem was achieved by employing the pseudorotation concept. The empirical potential surface was obtained by statistical treatment of 743 independent conformations from the Cambridge Structural Database. The theoretical potential surface was obtained by molecular mechanics. The minimal-energy conformation is gauche with the Co atom on the two-fold axis. Conformational flexibility also includes an envelope conformation with the N atom bent out of the plane. The transition between the mirror-image symmetrical conformations can occur by a pseudorotation pathway and is accompanied by increased planarity of the ring. The transition state is an envelope conformation with an out-plane Co atom.
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Bierzyński, A. "Methods of peptide conformation studies." Acta Biochimica Polonica 48, no. 4 (December 31, 2001): 1091–99. http://dx.doi.org/10.18388/abp.2001_3870.
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In solution most of the peptides assume multiple flexible conformations. Determination of the dominant conformers and evaluation of their populations is the aim of peptide conformation studies, in which theoretical and experimental methods play complementary roles. Molecular dynamics or Monte Carlo methods are quite effective in searching the conformational space accessible to a peptide but they are not able to estimate, precisely enough, the populations of various conformations. Therefore, they must be supplemented by experimental data. In this paper, a short review of the experimental methods, most widely used in peptide conformational studies, is presented. Among them NMR plays the leading role. Valuable information is also obtained from hydrogen exchange, fluorescence resonance energy transfer, and circular dichroism measurements. The advantages and shortcomings of these methods are discussed.
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Liljas, Anders, Arnthor Ævarsson, Salam Al-Karadaghi, Maria Garber, Julia Zheltonosova, and Evgeni Brazhnikov. "Crystallographic studies of elongation factor G." Biochemistry and Cell Biology 73, no. 11-12 (December 1, 1995): 1209–16. http://dx.doi.org/10.1139/o95-130.
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The elongation factors G (EF-G) and Tu (EF-Tu) go through a number of conformation states in their functional cycles. Since they both are GTPases, have similar G domains and domains II, and have similar interactions with the nucleotides, then GTP hydrolysis must occur in similar ways. The crystal structures of two conformational states are known for EF-G and three are known for EF-Tu. The conformations of EF-G∙GDP and EF-Tu∙GTP are closely related. EF-Tu goes through a large conformational change upon GTP cleavage. This conformational change is to a large extent due to an altered interaction between the G domain and domains II and III. A number of kirromycin-resistant mutations are situated at the interface between domains I and III. The interface between the G domain and domain V in EF-G corresponds with this dynamic interface in EF-Tu. The contact area in EF-G is small and dominated by interactions between charged amino acids, which are part of a system that is observed to undergo conformational changes. Furthermore, a number of fusidic acid resistant mutants have been identified in this area. All of this evidence makes it likely that EF-G undergoes a large conformational change in its functional cycle. If the structures and conformational states of the elongation factors are related to a scheme in which the ribosome oscillates between two conformations, the pretranslocational and posttranslocational states, a model is arrived at in which EF-Tu drives the reaction in one direction and EF-G in the opposite. This may lead to the consequence that the GTP state of one factor is similar to the GDP state of the other. At the GTP hydrolysis state, the structures of the factors will be close to superimposable.Key words: elongation factor G, elongation factor Tu, crystal structures, conformational changes, ribosomal conformation.
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Almahmoud, Suliman, Xiaofang Wang, Jonathan L. Vennerstrom, and Haizhen A. Zhong. "Conformational Studies of Glucose Transporter 1 (GLUT1) as an Anticancer Drug Target." Molecules 24, no. 11 (June 7, 2019): 2159. http://dx.doi.org/10.3390/molecules24112159.
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Glucose transporter 1 (GLUT1) is a facilitative glucose transporter overexpressed in various types of tumors; thus, it has been considered as an important target for cancer therapy. GLUT1 works through conformational switching from an outward-open (OOP) to an inward-open (IOP) conformation passing through an occluded conformation. It is critical to determine which conformation is preferred by bound ligands because the success of structure-based drug design depends on the appropriate starting conformation of the target protein. To find out the most favorable GLUT 1 conformation for ligand binding, we ran systemic molecular docking studies for different conformations of GLUT1 using known GLUT1 inhibitors. Our data revealed that the IOP is the preferred conformation and that residues Phe291, Phe379, Glu380, Trp388, and Trp412 may play critical roles in ligand binding to GLUT1. Our data suggests that conformational differences in these five amino acids in the different conformers of GLUT1 may be used to design ligands that inhibit GLUT1.
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Solopova, O. N., L. P. Pozdnyakova, N. E. Varlamov, M. N. Bokov, E. V. Morozkina, Т. А. Yagudin, and P. G. Sveshnikov. "Conformational Differences between Active Angiotensins and Their Inactive Precursors." Acta Naturae 4, no. 1 (March 15, 2012): 74–77. http://dx.doi.org/10.32607/20758251-2012-4-1-74-77.
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The peptide conformation in the context of a protein polypeptide chain is influenced by proximal amino acid residues. However, the mechanisms of this interference remain poorly understood. We studied the conformation of angiotensins 1, 2 and 3, which are produced naturally in a sequential fashion from a precursor protein angiotensinogen and contain an identical peptide core structure. Using the example of angiotensins 1, 2 and 3, it was shown that similar amino acid sequences may have significant conformational differences in various molecules. In order to assess the conformational changes, we developed a panel of high-affinity mouse monoclonal antibodies against angiotensins 1, 2 and 3 and studied their cross-reactivity in indirect and competitive ELISAs. It was found that the conformations of inactive angiotensin1 and the corresponding fragment of angiotensinogen are similar; the same is true for the conformations of active angiotensins 2 and 3, whereas the conformations of homologous fragments in the active and inactive angiotensins differ significantly.
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Kotovych, George, John R. Cann, John M. Stewart, and Hitoshi Yamamoto. "NMR and CD conformational studies of bradykinin and its agonists and antagonists: application to receptor binding." Biochemistry and Cell Biology 76, no. 2-3 (May 1, 1998): 257–66. http://dx.doi.org/10.1139/o98-028.
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Most physiological processes are regulated by peptides that perform their functions by interacting with specific receptors on cells. Specific conformations of the peptides are required for correct interactions to take place, and a knowledge of the biologically important conformation is vital for the understanding of biological function. Over the last few years extensive studies using nuclear magnetic resonance and circular dichroism have been carried out on bradykinin (Arg1-Pro2-Pro3-Gly4-Phe5-Ser6-Pro7-Phe8-Arg9) and its antagonists with the objective of developing new drugs to combat severe pathologies associated with its production. In the present review, these techniques for the determination of peptide conformation are reviewed and applied to the study of bradykinin and its antagonists. Modeling of these conformational data in the presence of the B2 receptor or an antibody allows the biologically active conformations to be deduced and these are presented in this review.Key words: bradykinin antagonists, conformational analysis, NMR, CD, B2 receptor binding.
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Walsh, Daniel J., Abigail M. Schwind, Geoffrey P. Noble, and Surachai Supattapone. "Conformational diversity in purified prions produced in vitro." PLOS Pathogens 19, no. 1 (January 10, 2023): e1011083. http://dx.doi.org/10.1371/journal.ppat.1011083.
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Prion diseases are caused by misfolding of either wild-type or mutant forms of the prion protein (PrP) into self-propagating, pathogenic conformers, collectively termed PrPSc. Both wild-type and mutant PrPSc molecules exhibit conformational diversity in vivo, but purified prions generated by the serial protein misfolding cyclic amplification (sPMCA) technique do not display this same diversity in vitro. This discrepancy has left a gap in our understanding of how conformational diversity arises at the molecular level in both types of prions. Here, we use continuous shaking instead of sPMCA to generate conformationally diverse purified prions in vitro. Using this approach, we show for the first time that wild type prions initially seeded by different native strains can propagate as metastable PrPSc conformers with distinguishable strain properties in purified reactions containing a single active cofactor. Propagation of these metastable PrPSc conformers requires appropriate shaking conditions, and changes in these conditions cause all the different PrPSc conformers to converge irreversibly into the same single conformer as that produced in sPMCA reactions. We also use continuous shaking to show that two mutant PrP molecules with different pathogenic point mutations (D177N and E199K) adopt distinguishable PrPSc conformations in reactions containing pure protein substrate without cofactors. Unlike wild-type prions, the conformations of mutant prions appear to be dictated by substrate sequence rather than seed conformation. Overall, our studies using purified substrates in shaking reactions show that wild-type and mutant prions use fundamentally different mechanisms to generate conformational diversity at the molecular level.
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Ping, Jie, Pei Hao, Yi-Xue Li, and Jing-Fang Wang. "Molecular Dynamics Studies on the Conformational Transitions of Adenylate Kinase: A Computational Evidence for the Conformational Selection Mechanism." BioMed Research International 2013 (2013): 1–7. http://dx.doi.org/10.1155/2013/628536.
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Escherichia coliadenylate kinase (ADK) is a monomeric phosphotransferase enzyme that catalyzes reversible transfer of phosphoryl group from ATP to AMP with a large-scale domain motion. The detailed mechanism for this conformational transition remains unknown. In the current study, we performed long time-scale molecular dynamics simulations on both open and closed states of ADK. Based on the structural analyses of the simulation trajectories, we detected over 20 times conformational transitions between the open and closed states of ADK and identified two novel conformations as intermediate states in the catalytic processes. With these findings, we proposed a possible mechanism for the large-scale domain motion ofEscherichia coliADK and its catalytic process: (1) the substrate free ADK adopted an open conformation; (2) ATP bound with LID domain closure; (3) AMP bound with NMP domain closure; (4) phosphoryl transfer occurred with ATP, and AMP converted into two ADPs, and no conformational transition was detected in the enzyme; (5) LID domain opened with one ADP released; (6) another ADP released with NMP domain open. As both open and closed states sampled a wide range of conformation transitions, our simulation strongly supported the conformational selection mechanism forEscherichia coliADK.
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Mizutani, Tadashi, and Shigeyuki Yagi. "Linear tetrapyrroles as functional pigments in chemistry and biology." Journal of Porphyrins and Phthalocyanines 08, no. 03 (March 2004): 226–37. http://dx.doi.org/10.1142/s1088424604000210.
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1,19,21,24-tetrahydro-1,19-bilindione is the framework of pigments frequently found in nature, which includes biliverdin IX α, phytochromobilin and phycocyanobilin. 1,19-bilindiones have unique features such as (1) photochemical and thermal cis-trans isomerization, (2) excited energy transfer, (3) chiroptical properties due to the cyclic helical conformation, (4) redox activity, (5) coordination to various metals, and (6) reconstitution to proteins. 1,19-bilindione can adopt a number of conformations since it has exocyclic three double bonds and three single bonds that are rotatable thermally and photochemically. In solution, biliverdin and phycocyanobilin adopt a cyclic helical ZZZ, syn, syn, syn conformation, but other conformations are stabilized depending on the experimental conditions and substituents on the bilin framework. The conformational changes in 1,19-bilindiones are related to the biological functions of a photoreceptor protein, phytochrome. Structural and conformational studies of bilindiones are summarized both in solution and in protein. The conformational changes of bilins can be used for other functions such as a chirality sensor. The bilindiones and the zinc complexes of bilindiones can be employed as a chirality sensor due to the helically chiral structure and the dynamics of racemization of enantiomers. In this paper, we discuss the conformational equilibria and dynamics of bilindiones and its implications in photobiology and materials science.
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Toti, Kiran S., John R. Jimah, Veronica Salmaso, Jenny E. Hinshaw, and Kenneth A. Jacobson. "Synthesis and Effect of Conformationally Locked Carbocyclic Guanine Nucleotides on Dynamin." Biomolecules 12, no. 4 (April 16, 2022): 584. http://dx.doi.org/10.3390/biom12040584.
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Guanine nucleotides can flip between a North and South conformation in the ribose moiety. To test the enzymatic activity of GTPases bound to nucleotides in the two conformations, we generated methanocarba guanine nucleotides in the North or South envelope conformations, i.e., (N)-GTP and (S)-GTP, respectively. With dynamin as a model system, we examined the effects of (N)-GTP and (S)-GTP on dynamin-mediated membrane constriction, an activity essential for endocytosis. Dynamin membrane constriction and fission activity are dependent on GTP binding and hydrolysis, but the effect of the conformational state of the GTP nucleotide on dynamin activity is not known. After reconstituting dynamin-mediated lipid tubulation and membrane constriction in vitro, we observed via cryo-electron microscopy (cryo-EM) that (N)-GTP, but not (S)-GTP, enables the constriction of dynamin-decorated lipid tubules. These findings suggest that the activity of dynamin is dependent on the conformational state of the GTP nucleotide. However, a survey of nucleotide ribose conformations associated with dynamin structures in nature shows almost exclusively the (S)-conformation. The explanation for this mismatch of (N) vs. (S) required for GTP analogues in a dynamin-mediated process will be addressed in future studies.
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Brewer, Dyanne, Howard Hunter, and Gilles Lajoie. "NMR studies of the antimicrobial salivary peptides histatin 3 and histatin 5 in aqueous and nonaqueous solutions." Biochemistry and Cell Biology 76, no. 2-3 (May 1, 1998): 247–56. http://dx.doi.org/10.1139/o98-066.
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Conformational studies of the salivary peptides histatin 3 (H3) and histatin 5 (H5) were performed by NMR and circular dichroism (CD) in aqueous and nonaqueous solutions. Histatin 5 has no defined structure in H2O but adopts a more helical conformation in dimethyl sulfoxide and aqueous trifluoroethanol. This is in agreement with the CD analysis, which shows no secondary structure in H2O but increasing helical content in the presence of trifluoroethanol. CD analysis shows that H3 has less propensity to form a helical structure than H5 in similar conditions. The NMR analysis of H3 in H2O at pH 7.4 reveals that its conformational mobility is less than that of H5 as indicated by the observation of backbone cross peaks alphaN (i, i + 1) and NN (i, i + 1) and the slow exchanging amide protons in the C-terminus. However, H3 remains essentially unordered as suggested by the lack of longer range nuclear Overhauser effects (NOEs) in the NOESY spectrum. H3 becomes much more ordered in a mixture of 50:50 H2O - dimethyl sulfoxide as indicated by the numerous NOEs, including several side chain to side chain and side chain to backbone conectivities. Our data suggest that in these conditions H3 contains a turn in the region of K13 to K17 and possibly a 310 helix at the C-terminus. This study demonstrates that H3 and H5 are both conformationally mobile and that each adopt different types of conformations in aqueous and nonaqueous solutions.Key words: histatins, NMR, antimicrobial.
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Staś, Monika, Małgorzata A. Broda, and Dawid Siodłak. "Thiazole–amino acids: influence of thiazole ring on conformational properties of amino acid residues." Amino Acids 53, no. 5 (April 10, 2021): 673–86. http://dx.doi.org/10.1007/s00726-021-02974-0.
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Abstract Post-translational modified thiazole–amino acid (Xaa–Tzl) residues have been found in macrocyclic peptides (e.g., thiopeptides and cyanobactins), which mostly inhibit protein synthesis in Gram + bacteria. Conformational study of the series of model compounds containing this structural motif with alanine, dehydroalanine, dehydrobutyrine and dehydrophenylalanine were performed using DFT method in various environments. The solid-state crystal structure conformations of thiazole–amino acid residues retrieved from the Cambridge Structural Database were also analysed. The studied structural units tend to adopt the unique semi-extended β2 conformation; which is stabilised mainly by N–H⋯NTzl hydrogen bond, and for dehydroamino acids also by π-electron conjugation. The conformational preferences of amino acids with a thiazole ring were compared with oxazole analogues and the role of the sulfur atom in stabilising the conformations of studied peptides was discussed.
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Terada, Yukimasa, Tomoo Matsuura, Yukari Mori, and Shosuke Yamamura. "Theoretical studies of model compounds of lathyrane-type diterpenes." Canadian Journal of Chemistry 82, no. 1 (January 1, 2004): 11–18. http://dx.doi.org/10.1139/v03-171.
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The conformation of the 11-membered ring of the lathyrane skeleton has been investigated using NMR spectra and theoretical calculations. Some other skeletons, such as jatrophane, jatrapholane, and tigliane, seem to be derived from this framework, and the conformation is important in connection with the configuration of the resultant diterpenes. The conformation of lathyrane is principally defined by the orientation of the two methyl groups; namely, the methyl groups on C1 and C6 directed above or below the ring plane. Theoretical calculations revealed that the predominant conformation is altered depending on the oxygen functional groups on the ring. As far as the bond lengths, bond angles, and dihedral angles are concerned, all calculation methods afforded reasonable results. In contrast, as regards conformational stability, only the ab initio molecular orbital method (RHF/6-31G*) predicted the most stable conformation, consistent with NOE experiments. On the other hand, the stable conformations predicted by the ab initio method (RHF/STO-3G), the semi-empirical molecular orbital method (MOPAC(PM3)), and the molecular mechanics calculations (MM3) did not necessarily agree with the conformers suggested by the NOE experiments.Key words: ab initio MO, semi-empirical MO, molecular mechanics, 11-membered ring conformation, NOE.
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Bojarska, Joanna, Waldemar Maniukiewicz, Andrzej Fruziński, Lesław Sieroń, and Milan Remko. "Captopril and its dimer captopril disulfide: comparative structural and conformational studies." Acta Crystallographica Section C Structural Chemistry 71, no. 3 (February 18, 2015): 199–203. http://dx.doi.org/10.1107/s2053229615002582.
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The crystal structures of captopril {systematic name: (2S)-1-[(2S)-2-methyl-3-sulfanylpropanoyl]pyrrolidine-2-carboxylic acid}, C9H15NO3S, (1), and its dimer disulfide metabolite, 1,1′-{disulfanediylbis[(2S)-2-methyl-1-oxopropane-3,1-diyl]}bis-L-proline, C18H28N2O6S2, (2), were determined by single-crystal X-ray diffraction analysis. Compound (1) crystallizes in the orthorhombic space groupP212121, while compound (2) crystallizes in the monoclinic space groupP21, both with one molecule per asymmetric unit. The molecular geometries of (1) and (2) are quite similar, but certain differences appear in the conformations of the five-membered proline rings and the side chains containing the sulfhydryl group. The proline ring adopts an envelope conformation in (1), while in (2) it exists in envelope and slightly deformed half-chair conformations. The conformation adopted by the side chain is extended in (1) and folded in (2). A minimum-energy conformational search using Monte Carlo methods in the aqueous phase reveals that the optimized conformations of the title compounds differ from those determined crystallographically, which depend on their immediate environment. Intermolecular O—H...O and relatively weak C—H...O interactions seem to be effective in both structures and, together with S—H...O and C—H...S contacts, they create three-dimensional networks.
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Xu, Xiaojun, Tao Yu, and Shi-Jie Chen. "Understanding the kinetic mechanism of RNA single base pair formation." Proceedings of the National Academy of Sciences 113, no. 1 (December 22, 2015): 116–21. http://dx.doi.org/10.1073/pnas.1517511113.
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RNA functions are intrinsically tied to folding kinetics. The most elementary step in RNA folding is the closing and opening of a base pair. Understanding this elementary rate process is the basis for RNA folding kinetics studies. Previous studies mostly focused on the unfolding of base pairs. Here, based on a hybrid approach, we investigate the folding process at level of single base pairing/stacking. The study, which integrates molecular dynamics simulation, kinetic Monte Carlo simulation, and master equation methods, uncovers two alternative dominant pathways: Starting from the unfolded state, the nucleotide backbone first folds to the native conformation, followed by subsequent adjustment of the base conformation. During the base conformational rearrangement, the backbone either retains the native conformation or switches to nonnative conformations in order to lower the kinetic barrier for base rearrangement. The method enables quantification of kinetic partitioning among the different pathways. Moreover, the simulation reveals several intriguing ion binding/dissociation signatures for the conformational changes. Our approach may be useful for developing a base pair opening/closing rate model.
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Kline, Paul C., Anthony S. Serianni, Shaw-Guang Huang, Michael Hayes, and Robert Barker. "1H–1H internuclear distance measurements in carbohydrates: proton transient nuclear Overhauser enhancement and spin-lattice relaxation in (13C)- and (2H)-substituted compounds." Canadian Journal of Chemistry 68, no. 12 (December 1, 1990): 2171–82. http://dx.doi.org/10.1139/v90-333.
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Proton transient nuclear Overhauser enhancement (TnOe) and spin-lattice relaxation times (T1) have been used to evaluate the conformations of several monosaccharides and disaccharides containing (13C) and (2H) substitution. Absolute 1H–1H internuclear distances were determined by TnOe and DESERT (deuterium substitution effects on relaxation times) experiments on conformationally rigid methyl β-D-galactopyranoside and α- and β-D-xyloses, respectively. The DESERT method was extended to examine O-glycoside conformation in two blood-group disaccharides that were prepared enzymically with (13C) and (or) (2H) substitution. Preferred disaccharide conformations deduced from these distance measurements are compared to those determined from 13C–13C and 13C–1H spin coupling constants, theoretical calculations, and crystallographic studies. Keywords: TnOe, DESERT, carbohydrate conformation.
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WANG, DI-FEI, and YUN-DONG WU. "A THEORETICAL COMPARISON OF CONFORMATIONAL FEATURES OF CALIX[4]AROMATICS." Journal of Theoretical and Computational Chemistry 03, no. 01 (March 2004): 51–68. http://dx.doi.org/10.1142/s0219633604000908.
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Although there are tremendous studies about the conformational feature of calix[4]arenes and its analogies, no theoretical study has been done systematically about why some structural modifications could completely lead to a change of conformational preference. For example, calix[4]arene 1 adopts a cone conformation while its analogue calix[4]pyrrole 7 only adopts a 1,3-alternate conformation. So if this is only because of the effect of OH—OH hydrogen bonds, then why does O-methyl substituted calix[4]arene 2 still has cone conformation? In this paper, the conformational features of a series of seven calix[4]aromatics, calix[4]arene and calix[4]pyrrole related structures, have been investigated at BLYP/6–31G* level both in the gas phase and in CH 2 Cl 2 solution. The calculations demonstrated that three main factors influence the conformational preference of these calix[4]aromatics, i.e. the intramolecular hydrogen bond, the adjacent ring-ring electrostatic interaction and the intrinsic flexibility of the [14] metacyclophane framework. Calix[4]benzene 3 and calix[4]pyridine 4 have little conformational preferences due to their flexible [14] metacyclophane framework, the lack of hydrogen-bonding interactions and weak ring-ring electrostatic interactions. In contrast, calix[4]aromatics 1 and 5–7 have either intramolecular hydrogen bonds (1) or ring-ring electrostatic interactions (5–7). Consequently, calix[4]arene 1 has the cone preference and calix[4]pyrrole, calix[4]furan, and calixthiophene (5–7) have the 1,3-alternate preference. Methoxy calix[4]arene prefers a cone or partial cone conformation, because the 1,3-alternate and 1,2-alternate conformations are destabilized by electrostatic repulsions involving the methoxy group and the adjacent phenyl ring.
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Gerhardt, Valeska, Maya Tutughamiarso, and Michael Bolte. "Conformational studies of hydantoin-5-acetic acid and orotic acid." Acta Crystallographica Section C Crystal Structure Communications 68, no. 2 (January 18, 2012): o92—o98. http://dx.doi.org/10.1107/s0108270112001151.
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Hydantoin-5-acetic acid [2-(2,5-dioxoimidazolidin-4-yl)acetic acid] and orotic acid (2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxylic acid) each contain one rigid acceptor–donor–acceptor hydrogen-bonding site and a flexible side chain, which can adopt different conformations. Since both compounds may be used as coformers for supramolecular complexes, they have been crystallized in order to examine their conformational preferences, giving solvent-free hydantoin-5-acetic acid, C5H6N2O4, (I), and three crystals containing orotic acid, namely, orotic acid dimethyl sulfoxide monosolvate, C5H4N2O4·C2H6OS, (IIa), dimethylammonium orotate–orotic acid (1/1), C2H8N+·C5H3N2O4−·C5H4N2O4, (IIb), and dimethylammonium orotate–orotic acid (3/1), 3C2H8N+·3C5H3N2O4−·C5H4N2O4, (IIc). The crystal structure of (I) shows a three-dimensional network, with the acid function located perpendicular to the ring. Interestingly, the hydroxy O atom acts as an acceptor, even though the carbonyl O atom is not involved in any hydrogen bonds. However, in (IIa), (IIb) and (IIc), the acid functions are only slightly twisted out of the ring planes. All H atoms of the acidic functions are directed away from the rings and, with respect to the carbonyl O atoms, they show an antiperiplanar conformation in (I) and synperiplanar conformations in (IIa), (IIb) and (IIc). Furthermore, in (IIa), (IIb) and (IIc), different conformations of the acid O=C—C—N torsion angle are observed, leading to different hydrogen-bonding arrangements depending on their conformation and composition.
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Li, Haiyan, Zanxia Cao, Guodong Hu, Liling Zhao, Chunling Wang, and Jihua Wang. "Ligand-induced structural changes analysis of ribose-binding protein as studied by molecular dynamics simulations." Technology and Health Care 29 (March 25, 2021): 103–14. http://dx.doi.org/10.3233/thc-218011.
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BACKGROUND: The ribose-binding protein (RBP) from Escherichia coli is one of the representative structures of periplasmic binding proteins. Binding of ribose at the cleft between two domains causes a conformational change corresponding to a closure of two domains around the ligand. The RBP has been crystallized in the open and closed conformations. OBJECTIVE: With the complex trajectory as a control, our goal was to study the conformation changes induced by the detachment of the ligand, and the results have been revealed from two computational tools, MD simulations and elastic network models. METHODS: Molecular dynamics (MD) simulations were performed to study the conformation changes of RBP starting from the open-apo, closed-holo and closed-apo conformations. RESULTS: The evolution of the domain opening angle θ clearly indicates large structural changes. The simulations indicate that the closed states in the absence of ribose are inclined to transition to the open states and that ribose-free RBP exists in a wide range of conformations. The first three dominant principal motions derived from the closed-apo trajectories, consisting of rotating, bending and twisting motions, account for the major rearrangement of the domains from the closed to the open conformation. CONCLUSIONS: The motions showed a strong one-to-one correspondence with the slowest modes from our previous study of RBP with the anisotropic network model (ANM). The results obtained for RBP contribute to the generalization of robustness for protein domain motion studies using either the ANM or PCA for trajectories obtained from MD.
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Vill, V., and J. Thiem. "Flüssigkristalle mit monosubstituierten alicyclischen und heteroalicyclischen Ringen." Zeitschrift für Naturforschung A 45, no. 11-12 (December 1, 1990): 1345–48. http://dx.doi.org/10.1515/zna-1990-11-1219.
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AbstractTwenty two liquid crystalline mono-substituted cyclopentanes and cyclohexanes including their oxygen analogues were prepard and studied. Smectic phases with clearing temperatures ≦ 80 °C were observed, and these do not differ considerably between the esters of the more flexible five-membered ring derivatives and those of the conformationally more rigid six-membered rings. In case of the latter, decreasing clearing points are observed with increasing ratios of the axial conformation (static conformational effect). Altogether rather low clearing points are observed, which may be interpreted by a dynamic conformational effect owing to which fast ring inversion causes the compounds to appear in a bulkier shape, and this results in a disadvantageous packing in the mesophase.
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Cai, Xinming, Daniel Lietha, Derek F. Ceccarelli, Andrei V. Karginov, Zenon Rajfur, Ken Jacobson, Klaus M. Hahn, Michael J. Eck, and Michael D. Schaller. "Spatial and Temporal Regulation of Focal Adhesion Kinase Activity in Living Cells." Molecular and Cellular Biology 28, no. 1 (October 27, 2007): 201–14. http://dx.doi.org/10.1128/mcb.01324-07.
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ABSTRACT Focal adhesion kinase (FAK) is an essential kinase that regulates developmental processes and functions in the pathology of human disease. An intramolecular autoinhibitory interaction between the FERM and catalytic domains is a major mechanism of regulation. Based upon structural studies, a fluorescence resonance energy transfer (FRET)-based FAK biosensor that discriminates between autoinhibited and active conformations of the kinase was developed. This biosensor was used to probe FAK conformational change in live cells and the mechanism of regulation. The biosensor demonstrates directly that FAK undergoes conformational change in vivo in response to activating stimuli. A conserved FERM domain basic patch is required for this conformational change and for interaction with a novel ligand for FAK, acidic phospholipids. Binding to phosphatidylinositol 4,5-bisphosphate (PIP2)-containing phospholipid vesicles activated and induced conformational change in FAK in vitro, and alteration of PIP2 levels in vivo changed the level of activation of the conformational biosensor. These findings provide direct evidence of conformational regulation of FAK in living cells and novel insight into the mechanism regulating FAK conformation.
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Sassa, S., O. Sugita, N. Ohnuma, S. Imajo, T. Okumura, T. Noguchi, and A. Kappas. "Studies of the influence of chloro-substituent sites and conformational energy in polychlorinated biphenyls on uroporphyrin formation in chick-embryo liver cell cultures." Biochemical Journal 235, no. 1 (April 1, 1986): 291–96. http://dx.doi.org/10.1042/bj2350291.
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Treatment of cultured chick-embryo liver cells with polychlorinated biphenyls (PCB) results in decreased uroporphyrinogen decarboxylase activity and increased uroporphyrin accumulation. In the present study we examined the effect of the chloro- or bromo-substituent sites in biphenyls (BP) on uroporphyrin accumulation in cultured hepatocytes and the three-dimensional structure of these congeners determined by molecular orbital calculations using a MNDO (‘modified neglect of diatomic overlap’) method. Among 20 congeners examined, those which were effective in stimulating porphyrin accumulation contained at least two Cl or Br atoms at the lateral adjacent positions in each phenyl ring, e.g. 3,4,3′,4′-tetrachloro-, 2,4,3′,4′-tetrachloro-, 3,4,5,3′,4′,5′-hexachloro- and 3,4,5,3′,4′,5′-hexabromobiphenyl, whereas those which contained less than two halogen atoms or more than three halogen atoms in each phenyl ring or those which contained halogen atoms at 2,2′-positions were not effective. On the basis of the conformational energy (delta E, difference from the most stable conformational energy), which is calculated as a function of the dihedral angle (theta) between the two phenyl rings, biphenyl congeners can be classified into four groups with different conformations. The conformation of active PCB was relatively flexible, whereas inactive species had a rigidly angulated conformation. Furthermore, the calculated probability of the conformation distribution for each congener indicated that the probability of co-planarity was higher for active biphenyls than for inactive congeners. These structural characteristics suggest the significance of both the chloro-substituent sites and the conformational energy reflecting the phenyl-ring twist angles in determining the inhibitory effect of PCB on uroporphyrinogen decarboxylase activity.
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Berman, Andrea J., Anne R. Gooding, and Thomas R. Cech. "Tetrahymena Telomerase Protein p65 Induces Conformational Changes throughout Telomerase RNA (TER) and Rescues Telomerase Reverse Transcriptase and TER Assembly Mutants." Molecular and Cellular Biology 30, no. 20 (August 16, 2010): 4965–76. http://dx.doi.org/10.1128/mcb.00827-10.
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ABSTRACT The biogenesis of the Tetrahymena telomerase ribonucleoprotein particle (RNP) is enhanced by p65, a La family protein. Single-molecule and biochemical studies have uncovered a hierarchical assembly of the RNP, wherein the binding of p65 to stems I and IV of telomerase RNA (TER) causes a conformational change that facilitates the subsequent binding of telomerase reverse transcriptase (TERT) to TER. We used purified p65 and variants of TERT and TER to investigate the conformational rearrangements that occur during RNP assembly. Nuclease protection assays and mutational analysis revealed that p65 interacts with and stimulates conformational changes in regions of TER beyond stem IV. Several TER mutants exhibited telomerase activity only in the presence of p65, revealing the importance of p65 in promoting the correct RNP assembly pathway. In addition, p65 rescued TERT assembly mutants but not TERT activity mutants. Taken together, these results suggest that p65 stimulates telomerase assembly and activity in two ways. First, by sequestering stems I and IV, p65 limits the ensemble of structural conformations of TER, thereby presenting TERT with the active conformation of TER. Second, p65 acts as a molecular buttress within the assembled RNP, mutually stabilizing TER and TERT in catalytically active conformations.
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Wu, Si, Liu Hong, Yuqing Wang, Jieqiong Yu, Jie Yang, Jie Yang, Hong Zhang, and Sarah Perrett. "Kinetics of the conformational cycle of Hsp70 reveals the importance of the dynamic and heterogeneous nature of Hsp70 for its function." Proceedings of the National Academy of Sciences 117, no. 14 (March 20, 2020): 7814–23. http://dx.doi.org/10.1073/pnas.1914376117.
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Hsp70 is a conserved molecular chaperone that plays an indispensable role in regulating protein folding, translocation, and degradation. The conformational dynamics of Hsp70 and its regulation by cochaperones are vital to its function. Using bulk and single-molecule fluorescence resonance energy transfer (smFRET) techniques, we studied the interdomain conformational distribution of human stress-inducible Hsp70A1 and the kinetics of conformational changes induced by nucleotide and the Hsp40 cochaperone Hdj1. We found that the conformations between and within the nucleotide- and substrate-binding domains show heterogeneity. The conformational distribution in the ATP-bound state can be induced by Hdj1 to form an “ADP-like” undocked conformation, which is an ATPase-stimulated state. Kinetic measurements indicate that Hdj1 binds to monomeric Hsp70 as the first step, then induces undocking of the two domains and closing of the substrate-binding cleft. Dimeric Hdj1 then facilitates dimerization of Hsp70 and formation of a heterotetrameric Hsp70–Hsp40 complex. Our results provide a kinetic view of the conformational cycle of Hsp70 and reveal the importance of the dynamic nature of Hsp70 for its function.
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Bharathikumar, V. M., Kris Barreto, Marciano D. Reis, John F. Decoteau, and C. Ronald Geyer. "Genetic Screen to Isolate “Lariat” Peptides for Characterizing ABL Kinase Activity and Conformation." Blood 116, no. 21 (November 19, 2010): 438. http://dx.doi.org/10.1182/blood.v116.21.438.438.
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Abstract Abstract 438 Type II Abl kinase inhibitors such as imatinib achieve high selectivity by specifically targeting the inactive Abl/c-Kit conformation. However, these inhibitors are prone to inactivation by resistance mutations that cause conformational changes. A better understanding of mutant Abl conformations would provide information to design inhibitors that recognize multiple states of Abl with lower rates of resistance. To more easily examine Abl kinase conformations, conformer specific reagents are needed that are (i) easily generated against a given Abl conformation, (ii) compatible with genetic selections, in vivo and in vitro assays, and structural studies, and (iii) amenable to chemical synthesis. Recently, we developed a novel genetic screen for isolating “lariat” peptide inhibitors of protein function. Lariats are lactone-cyclized peptides that possess the above-mentioned characteristics and can be used to evaluate the function and therapeutic potential of proteins. Previously, we isolated specific lariat inhibitors against the inactive conformation of the bacterial repressor LexA. To obtain conformer specific lariats against Abl, we screened a combinatorial seven amino acid lariat library for interactions with the Abl SH1 domain using the yeast two-hybrid (Y2H) assay. We obtained two lariat peptides named A1 (SGWQRLPFEY) and A2 (SGWHRLSEEY) that interacted with the Abl SH1 domain. In vitro studies with purified Abl kinase demonstrated that the A1 lariat competitively inhibited ATP binding with an inhibitory constant of 5.95 μM. By performing site-saturation mutagenesis, we defined acceptable and tolerable substitutions at each position of the A1 lariat. To obtain tighter binding variants of the A1 lariat, we rationally designed mutations and constructed a second-generation lariat (GWQTLDWNY) with | 10 times higher affinity for Abl. We compared the affinity of the lariats for imatinib resistant Abl kinase mutants using the lariat Y2H binding assay. Mutations that (i) promote conformational dynamics of the kinase T315I), (ii) destabilize the Abl/c-Kit like inactive state (H396R), (iii) disrupt the flexibility or hydrophobicity of the lariat-binding pocket (E355G), and (iv) distort the ATP phosphate binding loop (Y253F), have a marked decrease in lariat affinity. Together, these results show that the lariat preferentially bound to the Abl/c-Kit like inactive conformation and act similarly to type II kinase inhibitors. A specificity screen against a panel of related and distant kinases also demonstrated the conformer specific nature of the lariats. We used lariats that recognized the Abl/c-Kit like inactive state to probe various conformations of Abl His396 mutants. His396 is located in the activation loop and does not alter the Abl/c-Kit like inactive form. His396Pro and His396Arg substitutions are clinically relevant imatinib resistant mutations that alter the conformation of Abl. Previous structural studies showed that the His396Pro mutation causes Abl to adopt the active conformation. It is hypothesized that the His396Arg mutation favors the inactive Src/Cdk like state. Using inactive conformation specific Abl lariats as probes, we showed that these lariats interact weakly with the His396Arg relative to His396, suggesting that this mutation destabilized the Abl/c-Kit like inactive state. We also showed that the lariats interacted stronger with a previously unreported His396Ile mutation than His396, indicating that His396Ile shifts Abl to a highly inactive conformation. Preliminary studies suggest that this residue plays a key role in determining the flexibility of the activation loop and hence the conformational state of Abl. These results provide information on the structure and sequence requirements for maintaining an auto-inhibited activation loop conformation. In summary, we isolated lariat peptide inhibitors against the Abl SH1 domain, characterized their mechanism of action, and improved their affinity for wild type and mutant Abl SH1domains. Additionally, we demonstrated that lariat peptides can be used as affinity reagents to probe conformational states of Abl. Disclosures: No relevant conflicts of interest to declare.
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Dobrovolska, Olena, Øyvind Strømland, Ørjan Sele Handegård, Martin Jakubec, Morten L. Govasli, Åge Aleksander Skjevik, Nils Åge Frøystein, Knut Teigen, and Øyvind Halskau. "Investigating the Disordered and Membrane-Active Peptide A-Cage-C Using Conformational Ensembles." Molecules 26, no. 12 (June 12, 2021): 3607. http://dx.doi.org/10.3390/molecules26123607.
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The driving forces and conformational pathways leading to amphitropic protein-membrane binding and in some cases also to protein misfolding and aggregation is the subject of intensive research. In this study, a chimeric polypeptide, A-Cage-C, derived from α-Lactalbumin is investigated with the aim of elucidating conformational changes promoting interaction with bilayers. From previous studies, it is known that A-Cage-C causes membrane leakages associated with the sporadic formation of amorphous aggregates on solid-supported bilayers. Here we express and purify double-labelled A-Cage-C and prepare partially deuterated bicelles as a membrane mimicking system. We investigate A-Cage-C in the presence and absence of these bicelles at non-binding (pH 7.0) and binding (pH 4.5) conditions. Using in silico analyses, NMR, conformational clustering, and Molecular Dynamics, we provide tentative insights into the conformations of bound and unbound A-Cage-C. The conformation of each state is dynamic and samples a large amount of overlapping conformational space. We identify one of the clusters as likely representing the binding conformation and conclude tentatively that the unfolding around the central W23 segment and its reorientation may be necessary for full intercalation at binding conditions (pH 4.5). We also see evidence for an overall elongation of A-Cage-C in the presence of model bilayers.
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Mlejnek, M., and S. Kuchinsky. "Volumetric Changes Between Different Conformations of Two SiOH Groups in SiO2 Glass." Advanced Materials Research 39-40 (April 2008): 89–92. http://dx.doi.org/10.4028/www.scientific.net/amr.39-40.89.
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We present numerical studies of possible modifications of SiOH groups in “wet” SiO2 glass with 193 nm laser irradiation. We focus on structural changes associated with two conformations: (i) two nearby hydrogen bonded SiOH groups, and (ii) oxygen triclusters, i.e. bridging oxygen forming a third covalent bond with a hydrogen atom. The energies of these two systems and the activation barrier of thermal relaxation between them identify the latter conformation as a candidate for a product formed under 193 nm laser exposure, when we consider the former conformation as an initial state. We investigate the effects of local volume changes associated with the changes in conformation and find it has non-negligible effect on the index of refraction. These conformational changes thus appear able to contribute to the permanent changes in index of refraction and absorption of the glass after UV irradiation.
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Gerbst, Alexey G., Vadim B. Krylov, and Nikolay E. Nifantiev. "Conformational changes in common monosaccharides caused by per-O-sulfation." Pure and Applied Chemistry 91, no. 7 (July 26, 2019): 1223–29. http://dx.doi.org/10.1515/pac-2018-1212.
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Abstract Polysulfated carbohydrates play an important role in many biological processes because of their ability to bind to various protein receptors such as different growth factors, blood coagulation factors, adhesion lectins etc. Precise information about spatial organization of sulfated derivatives is of high demand for molecular modelling of such interactions as well as for understanding of the mechanism of pyranoside-into-furanoside rearrangement. In this review we summarize the changes recently revealed for the conformations of common pyranosides and furanosides upon total O-sulfation which were studied by means of NMR spectroscopy as well as molecular modelling. It was found that pentoses, being more flexible, undergo complete conformational chair inversion. Meanwhile, for hexoses the situation strongly depends on the monosaccharide configuration. Conformational changes are most pronounced in gluco-compounds though quantum chemical calculations helped to establish that no complete chair inversion occurred. In furanosides distortions of two types were observed: either the ring conformation or the conformation of the side chain changed. The presented data may be used for the analysis of chemical, physical and biological properties of sulfated carbohydrates.
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Żyłka, Romuald, Justyna Kupiec, and Stanislaw Przestalski. "Peptides conformational changes of the erythrocyte membrane induced by organometallic tin compounds." Current Topics in Biophysics 34, no. 1 (January 1, 2011): 31–35. http://dx.doi.org/10.2478/v10214-011-0005-2.
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Peptides conformational changes of the erythrocyte membrane induced by organometallic tin compoundsThe paper presents the results of a study on the effect of selected organic chlorides of tin on peptide conformations of erythrocyte ghosts from pig blood. The following compounds were used: dibutyltin dichloride (DBT), tributyltin chloride (TBT), diphenyltin dichloride (DPhT) and triphenyltin chloride (TPhT). Peptide conformation changes were determined on the basis of measurements done with the ATR FTIR technique. This method made it possible to measure the percent share of a peptide with specified conformation in the whole amount of the peptides in the membranes studied. The investigation showed that all the tin organic compounds studied cause a several-percent decrease in the quantities of both the peptides with the α-helix and turn conformation, and about a 20% increase in ghost peptides with β-sheet conformation. It seems that the changes observed can cause disturbances in the function of proteins and, consequently, the activity of the membrane; and this may be one of the aspects of the toxic properties of organotins.
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Toepfer, Christopher N., Amanda C. Garfinkel, Gabriela Venturini, Hiroko Wakimoto, Giuliana Repetti, Lorenzo Alamo, Arun Sharma, et al. "Myosin Sequestration Regulates Sarcomere Function, Cardiomyocyte Energetics, and Metabolism, Informing the Pathogenesis of Hypertrophic Cardiomyopathy." Circulation 141, no. 10 (March 10, 2020): 828–42. http://dx.doi.org/10.1161/circulationaha.119.042339.
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Background: Hypertrophic cardiomyopathy (HCM) is caused by pathogenic variants in sarcomere protein genes that evoke hypercontractility, poor relaxation, and increased energy consumption by the heart and increased patient risks for arrhythmias and heart failure. Recent studies show that pathogenic missense variants in myosin, the molecular motor of the sarcomere, are clustered in residues that participate in dynamic conformational states of sarcomere proteins. We hypothesized that these conformations are essential to adapt contractile output for energy conservation and that pathophysiology of HCM results from destabilization of these conformations. Methods: We assayed myosin ATP binding to define the proportion of myosins in the super relaxed state (SRX) conformation or the disordered relaxed state (DRX) conformation in healthy rodent and human hearts, at baseline and in response to reduced hemodynamic demands of hibernation or pathogenic HCM variants. To determine the relationships between myosin conformations, sarcomere function, and cell biology, we assessed contractility, relaxation, and cardiomyocyte morphology and metabolism, with and without an allosteric modulator of myosin ATPase activity. We then tested whether the positions of myosin variants of unknown clinical significance that were identified in patients with HCM, predicted functional consequences and associations with heart failure and arrhythmias. Results: Myosins undergo physiological shifts between the SRX conformation that maximizes energy conservation and the DRX conformation that enables cross-bridge formation with greater ATP consumption. Systemic hemodynamic requirements, pharmacological modulators of myosin, and pathogenic myosin missense mutations influenced the proportions of these conformations. Hibernation increased the proportion of myosins in the SRX conformation, whereas pathogenic variants destabilized these and increased the proportion of myosins in the DRX conformation, which enhanced cardiomyocyte contractility, but impaired relaxation and evoked hypertrophic remodeling with increased energetic stress. Using structural locations to stratify variants of unknown clinical significance, we showed that the variants that destabilized myosin conformations were associated with higher rates of heart failure and arrhythmias in patients with HCM. Conclusions: Myosin conformations establish work-energy equipoise that is essential for life-long cellular homeostasis and heart function. Destabilization of myosin energy-conserving states promotes contractile abnormalities, morphological and metabolic remodeling, and adverse clinical outcomes in patients with HCM. Therapeutic restabilization corrects cellular contractile and metabolic phenotypes and may limit these adverse clinical outcomes in patients with HCM.
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Dubovskii, Peter V., Kira M. Dubova, Gleb Bourenkov, Vladislav G. Starkov, Anastasia G. Konshina, Roman G. Efremov, Yuri N. Utkin, and Valeriya R. Samygina. "Variability in the Spatial Structure of the Central Loop in Cobra Cytotoxins Revealed by X-ray Analysis and Molecular Modeling." Toxins 14, no. 2 (February 18, 2022): 149. http://dx.doi.org/10.3390/toxins14020149.
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Cobra cytotoxins (CTs) belong to the three-fingered protein family and possess membrane activity. Here, we studied cytotoxin 13 from Naja naja cobra venom (CT13Nn). For the first time, a spatial model of CT13Nn with both “water” and “membrane” conformations of the central loop (loop-2) were determined by X-ray crystallography. The “water” conformation of the loop was frequently observed. It was similar to the structure of loop-2 of numerous CTs, determined by either NMR spectroscopy in aqueous solution, or the X-ray method. The “membrane” conformation is rare one and, to date has only been observed by NMR for a single cytotoxin 1 from N. oxiana (CT1No) in detergent micelle. Both CT13Nn and CT1No are S-type CTs. Membrane-binding of these CTs probably involves an additional step—the conformational transformation of the loop-2. To confirm this suggestion, we conducted molecular dynamics simulations of both CT1No and CT13Nn in the Highly Mimetic Membrane Model of palmitoiloleoylphosphatidylglycerol, starting with their “water” NMR models. We found that the both toxins transform their “water” conformation of loop-2 into the “membrane” one during the insertion process. This supports the hypothesis that the S-type CTs, unlike their P-type counterparts, require conformational adaptation of loop-2 during interaction with lipid membranes.
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Fuller, Watson, Trevor Forsyth, and Arumugam Mahendrasingam. "Water–DNA interactions as studied by X–ray and neutron fibre diffraction." Philosophical Transactions of the Royal Society of London. Series B: Biological Sciences 359, no. 1448 (August 29, 2004): 1237–48. http://dx.doi.org/10.1098/rstb.2004.1501.
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X–ray fibre–diffraction studies indicate a high degree of stereochemical specificity in interactions between water and the DNA double helix. Evidence for this comes from data that show that the molecular conformations assumed by DNA in fibres are highly reproducible and that the hydration–driven transitions between these conformations are fully reversible. These conformational transitions are induced by varying the relative humidity of the fibre environment and hence its water content. Further evidence for stereochemical specificity comes from the observed dependence of the conformation assumed on the ionic content of the fibre and the nucleotide sequence of the DNA. For some transitions, information on stereochemical pathways has come from real–time X–ray fibre diffraction using synchrotron radiation; information on the location of water with respect to the double helix for a number of DNA conformations has come from neutron fibre diffraction. This structural information from fibre–diffraction studies of DNA is complemented by information from X–ray single–crystal studies of oligonucleotides. If the biochemical processes involving DNA have evolved to exploit the structural features observed in DNA fibres and oligonucleotide single crystals, the challenges in developing alternatives to a water environment can be expected to be very severe.
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Agaeva, G., G. Safarli, and N. Godjaev. "MOLECULAR MODELLİNG OF CONFORMATİONAL FLEXİBİLİTY OF HYLAMBATİN MOLECULE." Russian Journal of Biological Physics and Chemisrty 7, no. 2 (November 15, 2022): 194–98. http://dx.doi.org/10.29039/rusjbpc.2022.0502.
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The features of the spatial organization of the hylambatin molecule were investigated by methods of molecular mechanics and molecular dynamics. Hylambatin consists of twelve amino acid residues in the sequence: Asp-Pro-Pro-Asp-Pro-Asn-Arg-Phe-Tyr-Gly-Met-Met-NH2. Unlike all other tachykinins, hylambatin has a Met residue replacing the usual Leu at penultimate position. The tachykinin peptide hylambatin has been isolated and chemically characterized from methanol extracts of the skin of Hylambates maculatus, an African rhacophorid frog. It has been shown that intravenously administered hylambatin significantly increases the level of glucose and insulin in blood plasma. In this paper, the conformational flexibility of the hylambatin molecule was studied by methods of molecular mechanics and molecular dynamics. The conformational calculation of the peptide took into account non-valent and electrostatic interactions, hydrogen bonds and torsion potentials. Based on fragmentary analysis, stable spatial structures of the hylambatin dodecapeptide were determined, which can be represented as a set of conformations characterized by a relatively labile N-terminal tetrapeptide and a conformationally rigid C-terminal octapeptide. In the calculated stable conformational states, the effective interactions of the side chains of residues and hydrogen bonds were refined and energetically evaluated. It has been shown that the hylambatin molecule preferably forms practically isoenergetic conformations with various structural types at the N-end of the peptide chain, passing into the alpha helix at the C-end. By the method of molecular dynamics, the pattern of intramolecular mobility of stable conformations of the hylambatin molecule was modeled both in vacuum and surrounded by water molecules. Based on the calculated values of the dihedral angles, molecular models of energetically preferred conformational states of the hylambatin dodecapeptide were constructed.
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SENGE, MATHIAS O., INES BISCHOFF, NORA Y. NELSON, and KEVIN M. SMITH. "Synthesis, Reactivity and Structural Chemistry of 5,10,15,20-Tetraalkylporphyrins." Journal of Porphyrins and Phthalocyanines 03, no. 02 (February 1999): 99–116. http://dx.doi.org/10.1002/(sici)1099-1409(199902)3:2<99::aid-jpp109>3.0.co;2-6.
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The synthesis, reactivity and full characterization of a series of meso-tetraalkyl porphyrins and metalloporphyrins with R ≡ n-butyl (6), 2-methyl-propyl (7), isopropyl (8), l-ethyl-propyl (10) and tert-butyl (11) groups are reported. Derivatives of the last of these show considerably bathochromically shifted absorption bands and the crystal structure of Zn ( II )11(pyr) exhibits a severely ruffled macrocycle conformation. Systematic crystallographic studies of the porphyrins showed that the free base porphyrins with R ≡ n-butyl ( H 26), 2-methyl-propyl ( H 27) and 1-ethyl-propyl ( H 210) are planar. A larger conformational variety was found for the metal complexes. While most Ni ( II ) derivatives and Pd ( II )8 showed a ruffled macrocycle conformation with a degree of ruffling exceeding that of meso-unsubstituted porphyrins, both planar and non-planar forms were found for the related Cu ( II ) derivatives. The Zn ( II ) complexes of porphyrins with isopropyl or 1-ethyl-propyl exhibited conformations with variable degree of distortion. Together with comparative structures from the literature, this study provides experimental evidence that considerable conformational flexibility exists for meso-alkylporphyrins with substituents less bulky than tert-butyl groups.
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Park, Kunwoong, Byoung-Cheol Lee, and Hyun-Ho Lim. "Mutation of external glutamate residue reveals a new intermediate transport state and anion binding site in a CLC Cl−/H+ antiporter." Proceedings of the National Academy of Sciences 116, no. 35 (August 13, 2019): 17345–54. http://dx.doi.org/10.1073/pnas.1901822116.
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The CLC family of proteins are involved in a variety of physiological processes to control cellular chloride concentration. Two distinct classes of CLC proteins, Cl− channels and Cl−/H+ antiporters, have been functionally and structurally investigated over the last several decades. Previous studies have suggested that the conformational heterogeneity of the critical glutamate residue, Gluex, could explain the transport cycle of CLC-type Cl−/H+ antiporters. However, the presence of multiple conformations (Up, Middle, and Down) of the Gluex has been suggested from combined structural snapshots of 2 different CLC antiporters: CLC-ec1 from Escherichia coli and cmCLC from a thermophilic red alga, Cyanidioschyzon merolae. Thus, we aimed to investigate further the heterogeneity of Gluex-conformations in CLC-ec1, the most deeply studied CLC antiporter, at both functional and structural levels. Here, we show that the crystal structures of the Gluex mutant E148D and wild-type CLC-ec1 with varying anion concentrations suggest a structural intermediate, the “Midlow” conformation. We also found that an extra anion can be located above the external Cl−-binding site in the E148D mutant when the anion concentration is high. Moreover, we observed that a carboxylate in solution can occupy either the external or central Cl−-binding site in the ungated E148A mutant using an anomalously detectable short carboxylic acid, bromoacetate. These results lend credibility to the idea that the Gluex can take at least 3 distinct conformational states during the transport cycle of a single CLC antiporter.
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Frydenvang, K., and B. Jensen. "Conformational analysis of acetylcholine and related choline esters." Acta Crystallographica Section B Structural Science 52, no. 1 (February 1, 1996): 184–93. http://dx.doi.org/10.1107/s0108768195007567.
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The crystal structures of carbamoylcholine [2-(carbamoyloxy)-N,N,N-trimethylethanaminium] chloride, bromide and iodide, methoxycarbonylcholine [2-(methoxycarbonyloxy)-N,N,N-trimethylethanaminium] iodide, acetylcholine [2-(acetyloxy)-N,N,N-trimethylethanaminium] chloride and succinylcholine { 2,2′-[(1,4-dioxo-1,4-butanediyl)bis(oxy)]bis(N,N,N-trimethylethanaminium)} iodide have been redetermined at 105 K in order to obtain detailed and accurate information on the geometry of choline esters and to elucidate the conformationally dependent changes of geometry. The conformational flexibility and the preferred conformations are elucidated based on results obtained from X-ray crystallographic studies and molecular mechanics (MM2) calculations. The usefulness of molecular mechanics calculations for quaternary ammonium ions is discussed.
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Allman, Tim, and R. E. Lenkinski. "A conformational analysis of adriamycin based upon its 1H nuclear magnetic resonance spectrum in various solvents." Canadian Journal of Chemistry 65, no. 10 (October 1, 1987): 2405–10. http://dx.doi.org/10.1139/v87-401.
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The solution conformation of adriamycin was studied by 1H nuclear magnetic resonance spectroscopy. The hydrochloride was found to be rigid on the nmr time scale in each of CDCl3, DMF-d7, and DMSO-d6. The sugar and D rings were found to have the same conformations as were found previously by X-ray crystallography. Similar results were found for the free base in DMF-d7 and CDCl3 solutions although the free base was found to be conformationally mobile in acetone-d6 and CD3OD solutions.
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Tiwari-Woodruff, Seema K., Meng-chin A. Lin, Christine T. Schulteis, and Diane M. Papazian. "Voltage-Dependent Structural Interactions in the Shaker K+ Channel." Journal of General Physiology 115, no. 2 (January 18, 2000): 123–38. http://dx.doi.org/10.1085/jgp.115.2.123.
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Using a strategy related to intragenic suppression, we previously obtained evidence for structural interactions in the voltage sensor of Shaker K+ channels between residues E283 in S2 and R368 and R371 in S4 (Tiwari-Woodruff, S.K., C.T. Schulteis, A.F. Mock, and D.M. Papazian. 1997. Biophys. J. 72:1489–1500). Because R368 and R371 are involved in the conformational changes that accompany voltage-dependent activation, we tested the hypothesis that these S4 residues interact with E283 in S2 in a subset of the conformational states that make up the activation pathway in Shaker channels. First, the location of residue 283 at hyperpolarized and depolarized potentials was inferred by substituting a cysteine at that position and determining its reactivity with hydrophilic, sulfhydryl-specific probes. The results indicate that position 283 reacts with extracellularly applied sulfhydryl reagents with similar rates at both hyperpolarized and depolarized potentials. We conclude that E283 is located near the extracellular surface of the protein in both resting and activated conformations. Second, we studied the functional phenotypes of double charge reversal mutations between positions 283 and 368 and between 283 and 371 to gain insight into the conformations in which these positions approach each other most closely. We found that combining charge reversal mutations at positions 283 and 371 stabilized an activated conformation of the channel, and dramatically slowed transitions into and out of this state. In contrast, charge reversal mutations at positions 283 and 368 stabilized a closed conformation, which by virtue of the inferred position of 368 corresponds to a partially activated (intermediate) closed conformation. From these results, we propose a preliminary model for the rearrangement of structural interactions of the voltage sensor during activation of Shaker K+ channels.
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Kotmale, Amol S., Ekta Sangtani, Rajesh G. Gonnade, Dhiman Sarkar, Sachin Burade, Pattuparambil R. Rajamohanan, and Gangadhar J. Sanjayan. "Conformational studies of Ant–Pro motif-incorporated cyclic peptides: gramicidin S and avellanin." New Journal of Chemistry 42, no. 2 (2018): 1197–201. http://dx.doi.org/10.1039/c7nj03701e.
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Conformational studies suggest that an AntDPro motif-incorporated synthetic gramicidin S analog retains β-sheet conformation, while its truncated analog avellanin disturbs the β-sheet conformation.
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Kaplan, Gilad, Anna Roitburd-Berman, George K. Lewis, and Jonathan M. Gershoni. "Range of CD4-Bound Conformations of HIV-1 gp120, as Defined Using Conditional CD4-Induced Antibodies." Journal of Virology 90, no. 9 (February 17, 2016): 4481–93. http://dx.doi.org/10.1128/jvi.03206-15.
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ABSTRACTThe HIV envelope binds cellular CD4 and undergoes a range of conformational changes that lead to membrane fusion and delivery of the viral nucleocapsid into the cellular cytoplasm. This binding to CD4 reveals cryptic and highly conserved epitopes, the molecular nature of which is still not fully understood. The atomic structures of CD4 complexed with gp120 core molecules (a form of gp120 in which the V1, V2, and V3 loops and N and C termini have been truncated) have indicated that a hallmark feature of the CD4-bound conformation is the bridging sheet minidomain. Variations in the orientation of the bridging sheet hairpins have been revealed when CD4-liganded gp120 was compared to CD4-unliganded trimeric envelope structures. Hence, there appears to be a number of conformational transitions possible in HIV-1 monomeric gp120 that are affected by CD4 binding. The spectrum of CD4-bound conformations has been interrogated in this study by using a well-characterized panel of conditional, CD4-induced (CD4i) monoclonal antibodies (MAbs) that bind HIV-1 gp120 and its mutations under various conditions. Two distinct CD4i epitopes of the outer domain were studied: the first comprises the bridging sheet, while the second contains elements of the V2 loop. Furthermore, we show that the unliganded extended monomeric core of gp120 (coree) assumes an intermediate CD4i conformation in solution that further undergoes detectable rearrangements upon association with CD4. These discoveries impact both accepted paradigms concerning gp120 structure and the field of HIV immunogen design.IMPORTANCEElucidation of the conformational transitions that the HIV-1 envelope protein undergoes during the course of entry into CD4+cells is fundamental to our understanding of HIV biology. The binding of CD4 triggers a range of gp120 structural rearrangements that could present targets for future drug design and development of preventive vaccines. Here we have systematically interrogated and scrutinized these conformational transitions using a panel of antibody probes that share a specific preference for the CD4i conformations. These have been employed to study a collection of gp120 mutations and truncations. Through these analyses, we propose 4 distinct sequential steps in CD4i transitions of gp120 conformations, each defined by antibody specificities and structural requirements of the HIV envelope monomer. As a result, we not only provide new insights into this dynamic process but also define probes to further investigate HIV infection.
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Pallipurath, Anuradha R., Jonathan M. Skelton, Andrew Britton, Elizabeth A. Willneff, and Sven L. M. Schroeder. "Bulk and Surface Conformations in Solid-State Lovastatin: Spectroscopic and Molecular Dynamics Studies." Crystals 11, no. 5 (May 4, 2021): 509. http://dx.doi.org/10.3390/cryst11050509.
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Conformational flexibility in molecules can give rise to a range of functional group terminations at crystal surfaces and dynamic disorder in the bulk. In this work, we explore the conformational behavior of the drug molecule lovastatin in the crystallographically disordered solid and at crystal surfaces through a combination of computational modeling and spectroscopy. Gas-phase and periodic quantum-chemical calculations are used to study the potential energy surface associated with rotatable bonds to examine the disorder in bulk. These calculations are combined with vibrational and X-ray photoelectron spectroscopy measurements to obtain insight into the conformations in bulk and at the surface. Our MD simulations show that the bulk disorder is driven by cooperative motion of the butyl group on the S-butanoate moiety along one crystallographic direction beyond a unit cell. The calculations show that the O-H group can rotate relatively freely between two low-energy conformers in the gas phase but is locked in position by intermolecular H-bonding interactions in the bulk crystal, and we find tentative spectroscopic evidence for the second conformer being present at the surface. We also comment on the relative utility of these different techniques for studying molecular conformation in bulk and at surfaces and highlight possible areas for future developments.
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Papageorgiou, A. C., N. G. Oikonomakos, D. D. Leonidas, B. Bernet, D. Beer, and A. Vasella. "The binding of d-gluconohydroximo-1,5-lactone to glycogen phosphorylase. Kinetic, ultracentrifugation and crystallographic studies." Biochemical Journal 274, no. 2 (March 1, 1991): 329–38. http://dx.doi.org/10.1042/bj2740329.
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Combined kinetic, ultracentrifugation and X-ray-crystallographic studies have characterized the effect of the beta-glucosidase inhibitor gluconohydroximo-1,5-lactone on the catalytic and structural properties of glycogen phosphorylase. In the direction of glycogen synthesis, gluconohydroximo-1,5-lactone was found to competitively inhibit both the b (Ki 0.92 mM) and the alpha form of the enzyme (Ki 0.76 mM) with respect to glucose 1-phosphate in synergism with caffeine. In the direction of glycogen breakdown, gluconohydroximo-1,5-lactone was found to inhibit phosphorylase b in a non-competitive mode with respect to phosphate, and no synergism with caffeine could be demonstrated. Ultracentrifugation and crystallization experiments demonstrated that gluconohydroximo-1,5-lactone was able to induce dissociation of tetrameric phosphorylase alpha and stabilization of the dimeric T-state conformation. A crystallographic binding study with 100 mM-gluconohydroximo-1,5-lactone at 0.24 nm (2.4 A) resolution showed a major peak at the catalytic site, and no significant conformational changes were observed. Analysis of the electron-density map indicated that the ligand adopts a chair conformation. The results are discussed with reference to the ability of the catalytic site of the enzyme to distinguish between two or more conformations of the glucopyranose ring.
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Camacho, Inês S., Alina Theisen, Linus O. Johannissen, L. Aranzazú Díaz-Ramos, John M. Christie, Gareth I. Jenkins, Bruno Bellina, Perdita Barran, and Alex R. Jones. "Native mass spectrometry reveals the conformational diversity of the UVR8 photoreceptor." Proceedings of the National Academy of Sciences 116, no. 4 (January 4, 2019): 1116–25. http://dx.doi.org/10.1073/pnas.1813254116.
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UVR8 is a plant photoreceptor protein that regulates photomorphogenic and protective responses to UV light. The inactive, homodimeric state absorbs UV-B light, resulting in dissociation into monomers, which are considered to be the active state and comprise a β-propeller core domain and intrinsically disordered N- and C-terminal tails. The C terminus is required for functional binding to signaling partner COP1. To date, however, structural studies have only been conducted with the core domain where the terminal tails have been truncated. Here, we report structural investigations of full-length UVR8 using native ion mobility mass spectrometry adapted for photoactivation. We show that, while truncated UVR8 photoconverts from a single conformation of dimers to a single monomer conformation, the full-length protein exists in numerous conformational families. The full-length dimer adopts both a compact state and an extended state where the C terminus is primed for activation. In the monomer the extended C terminus destabilizes the core domain to produce highly extended yet stable conformations, which we propose are the fully active states that bind COP1. Our results reveal the conformational diversity of full-length UVR8. We also demonstrate the potential power of native mass spectrometry to probe functionally important structural dynamics of photoreceptor proteins throughout nature.
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Whelan, Donna R., Thomas J. Hiscox, Julian I. Rood, Keith R. Bambery, Don McNaughton, and Bayden R. Wood. "Detection of an en masse and reversible B- to A-DNA conformational transition in prokaryotes in response to desiccation." Journal of The Royal Society Interface 11, no. 97 (August 6, 2014): 20140454. http://dx.doi.org/10.1098/rsif.2014.0454.
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The role that DNA conformation plays in the biochemistry of cells has been the subject of intensive research since DNA polymorphism was discovered. B-DNA has long been considered the native form of DNA in cells although alternative conformations of DNA are thought to occur transiently and along short tracts. Here, we report the first direct observation of a fully reversible en masse conformational transition between B- and A-DNA within live bacterial cells using Fourier transform infrared (FTIR) spectroscopy. This biospectroscopic technique allows for non-invasive and reagent-free examination of the holistic biochemistry of samples. For this reason, we have been able to observe the previously unknown conformational transition in all four species of bacteria investigated. Detection of this transition is evidence of a previously unexplored biological significance for A-DNA and highlights the need for new research into the role that A-DNA plays as a cellular defence mechanism and in stabilizing the DNA conformation. Such studies are pivotal in understanding the role of A-DNA in the evolutionary pathway of nucleic acids. Furthermore, this discovery demonstrates the exquisite capabilities of FTIR spectroscopy and opens the door for further investigations of cell biochemistry with this under-used technique.
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Schaefer, Ted, Rudy Sebastian, Alberta Lemire, and Glenn H. Penner. "1H and 13C NMR studies of the conformational mobility of 1,2-dimethoxybenzene in solution." Canadian Journal of Chemistry 68, no. 8 (August 1, 1990): 1393–98. http://dx.doi.org/10.1139/v90-213.
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1H NMR and 13C NMR spectral data are presented for 1,2-dimethoxybenzene-α,α′-13C, as well as for a number of other anisole derivatives. For the title molecule, the coupling constants between the 13C nucleus in the side chain and the para ring proton or 13C nucleus in the benzene ring show that the expectation value of sin2 θ is very near 0.2 at 300 K, where θ is the angle by which the methoxy groups twist out of the aromatic plane. This value of [Formula: see text] is much larger than that of 0.05 for anisole in solution, emphasizing the greater conformational mobility of the methoxy groups in 1,2-dimethoxybenzene (DMB). Long-range coupling constants between the methyl and ring protons in DMB are also discussed and compared with those in anisole and some of its derivatives. The preponderance of conformations with large values of θ, thought to occur in the vapor, disappears in solution at ambient temperatures. Under these conditions, the molecule is perhaps best described as preferring a planar conformation in which, however, the methoxy groups undergo excursions in θ whose average value is near 25°. Keywords: 1,2-dimethoxybenzene, conformational behaviour, internal mobility, long-range coupling constants, 1H and 13C NMR.
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Freitas, Matheus Puggina de, and Teodorico de Castro Ramalho. "Employing conformational analysis in the molecular modeling of agrochemicals: insights on QSAR parameters of 2,4-D." Ciência e Agrotecnologia 37, no. 6 (December 2013): 485–94. http://dx.doi.org/10.1590/s1413-70542013000600001.
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A common practice to compute ligand conformations of compounds with various degrees of freedom to be used in molecular modeling (QSAR and docking studies) is to perform a conformational distribution based on repeated random sampling, such as Monte-Carlo methods. Further calculations are often required. This short review describes some methods used for conformational analysis and the implications of using selected conformations in QSAR. A case study is developed for 2,4-dichlorophenoxyacetic acid (2,4-D), a widely used herbicide which binds to TIR1 ubiquitin ligase enzyme. The use of such an approach and semi-empirical calculations did not achieve all possible minima for 2,4-D. In addition, the conformations and respective energies obtained by the semi-empirical AM1 method do not match the calculated trends obtained by a high level DFT method. Similar findings were obtained for the carboxylate anion, which is the bioactive form. Finally, the crystal bioactive structure of 2,4-D was not found as a minimum when using Monte-Carlo/AM1 and is similarly populated with another conformer in implicit water solution according to optimization at the B3LYP/aug-cc-pVDZ level. Therefore, quantitative structure-activity relationship (QSAR) methods based on three dimensional chemical structures are not fundamental to provide predictive models for 2,4-D congeners as TIR1 ubiquitin ligase ligands, since they do not necessarily reflect the bioactive conformation of this molecule. This probably extends to other systems.
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Sambasivam, Dhandayuthapani, Senthilkumar Sivanesan, Sayeeda Sultana, and Jayakumar Rajadas. "Conformational Preferences of Aβ25-35 and Aβ35-25 in Membrane Mimicking Environments." Protein & Peptide Letters 26, no. 5 (May 29, 2019): 386–90. http://dx.doi.org/10.2174/0929866526666190228122849.
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Background: The structural transition of aggregating Abeta peptides is the key event in the progression of Alzheimer’s Disease (AD). Objective: In the present work, the structural modifications of toxic Aβ25-35 and the scrambled Aβ35-25 were studied in Trifluoroethanol (TFE) and in aqueous SDS micelles. Methods: Using CD spectroscopic investigations, the conformational transition of Aβ25-35 and Aβ35-25 peptides were determined in different membrane mimicking environments such as TFE and SDS. An interval scan CD of the peptides on evaporation of TFE was performed. TFE titrations were carried out to investigate the intrinsic ability of the structural conformations of peptides. Results: We show by spectroscopic evidence that Aβ25-35 prefers beta sheet structures upon increasing TFE concentrations. On the other hand, the non-toxic scrambled Aβ35-25 peptide only undergoes a transition from random coil to α-helix conformation with increasing TFE. In the interval scan studies, Aβ25-35 did not show any structural transitions, whereas Aβ35-25 showed transition from α-helix to β-sheet conformation. In membrane simulating aqueous SDS micelles, Aβ25-35 showed a transition from random coil to α-helix while Aβ35-25 underwent transition from random coil to β-sheet conformation. Conclusion: Overall, the current results seek new insights into the structural properties of amyloidogenic and the truncated sequence in membrane mimicking solvents.
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Yamato, Takehiko, Koji Fujita, Keigo Futatsuki, and Hirohisa Tsuzuki. "Medium-sized cyclophanes. Part 53.1 Synthesis and conformational studies, and photoinduced cyclization of syn-[n.2]metacyclophanenes." Canadian Journal of Chemistry 78, no. 8 (August 1, 2000): 1089–99. http://dx.doi.org/10.1139/v00-110.
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A series of [n.2]metacyclophanenes (3) and (6) were prepared in good yields by a McMurry cyclization of 1,n-bis(3-acetyl-4-methoxyphenyl)alkanes (2) and 1,3-bis(3-formyl-4-methoxyphenyl)propane (5), respectively. Compounds 3b, 3c exist in the syn-conformation due to the steric repulsion between the methyl groups at the ethano bridge and the methoxy groups at the aromatic rings while compound 6 prefers the anti-conformation typical of [3.2]metacyclophanes. The assignment of syn-conformations has been confirmed by 1H NMR analyses and X-ray diffraction studies. Photoinduced transannular cyclization of [n.2]metacyclophanenes (3) and (6) in the presence of iodine as an oxidant afforded phenanthrene-anellated polycyclic aromatic hydrocarbons. Apparently, the rate of the photocyclization of anti-6 was found to be much faster than that of syn-3b and almost completed within 1 h. Thus, the different reactivities for the irradiation of syn- and anti-conformer were observed. The reason for the present preference for the formation of trans-dihydrophenanthrene rather than cis-dihydrophenanthrene as the intermediate might be attributable to the more stable chair form transition state than boat one and the conformational fixation to the chair form in the ground and transition state is possible in the anti-conformer.Key words: cyclophanes, strained molecule, McMurry reaction, CC coupling, conformation analysis, cyclizations, photolysis, transannular reactions, transition states.
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Krukenberg, Kristin A., Timothy O. Street, Laura A. Lavery, and David A. Agard. "Conformational dynamics of the molecular chaperone Hsp90." Quarterly Reviews of Biophysics 44, no. 2 (March 18, 2011): 229–55. http://dx.doi.org/10.1017/s0033583510000314.
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AbstractThe ubiquitous molecular chaperone Hsp90 makes up 1–2% of cytosolic proteins and is required for viability in eukaryotes. Hsp90 affects the folding and activation of a wide variety of substrate proteins including many involved in signaling and regulatory processes. Some of these substrates are implicated in cancer and other diseases, making Hsp90 an attractive drug target. Structural analyses have shown that Hsp90 is a highly dynamic and flexible molecule that can adopt a wide variety of structurally distinct states. One driving force for these rearrangements is the intrinsic ATPase activity of Hsp90, as seen with other chaperones. However, unlike other chaperones, studies have shown that the ATPase cycle of Hsp90 is not conformationally deterministic. That is, rather than dictating the conformational state, ATP binding and hydrolysis only shift the equilibria between a pre-existing set of conformational states. For bacterial, yeast and human Hsp90, there is a conserved three-state (apo–ATP–ADP) conformational cycle; however; the equilibria between states are species specific. In eukaryotes, cytosolic co-chaperones regulate the in vivo dynamic behavior of Hsp90 by shifting conformational equilibria and affecting the kinetics of structural changes and ATP hydrolysis. In this review, we discuss the structural and biochemical studies leading to our current understanding of the conformational dynamics of Hsp90, as well as the roles that nucleotide, co-chaperones, post-translational modification and substrates play. This view of Hsp90's conformational dynamics was enabled by the use of multiple complementary structural methods including, crystallography, small-angle X-ray scattering (SAXS), electron microscopy, Förster resonance energy transfer (FRET) and NMR. Finally, we discuss the effects of Hsp90 inhibitors on conformation and the potential for developing small molecules that inhibit Hsp90 by disrupting the conformational dynamics.