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1
Plater, M. John, Abbie J. Esslemont, and William T. A. Harrison. "Porous and Close Packed Supramolecular Assemblies from 2,4-Difluoronitrobenzene with Three Different Linkers and an n-Butylamine Cap." International Journal of Molecular Sciences 24, no. 19 (September 28, 2023): 14683. http://dx.doi.org/10.3390/ijms241914683.
Анотація:
A porous structure formed from sheets with cavities and two close packed structures were crystallised from building blocks prepared from 2,4-difluoronitrobenzene, a diamine linker and n-butylamine. The porous structure crystallised from a flexible building block prepared using 1,4-diaminobutane as linker. The close packed structures were prepared using either piperazine or 1,4-bis(aminomethyl)benzene as a linker and have less conformational freedom.
2
Thielen, Nathalie, Margot Neefjes, Renske Wiegertjes, Guus van den Akker, Elly Vitters, Henk van Beuningen, Esmeralda Blaney Davidson та ін. "Osteoarthritis-Related Inflammation Blocks TGF-β’s Protective Effect on Chondrocyte Hypertrophy via (de)Phosphorylation of the SMAD2/3 Linker Region". International Journal of Molecular Sciences 22, № 15 (29 липня 2021): 8124. http://dx.doi.org/10.3390/ijms22158124.
Анотація:
Osteoarthritis (OA) is a degenerative joint disease characterized by irreversible cartilage damage, inflammation and altered chondrocyte phenotype. Transforming growth factor-β (TGF-β) signaling via SMAD2/3 is crucial for blocking hypertrophy. The post-translational modifications of these SMAD proteins in the linker domain regulate their function and these can be triggered by inflammation through the activation of kinases or phosphatases. Therefore, we investigated if OA-related inflammation affects TGF-β signaling via SMAD2/3 linker-modifications in chondrocytes. We found that both Interleukin (IL)-1β and OA-synovium conditioned medium negated SMAD2/3 transcriptional activity in chondrocytes. This inhibition of TGF-β signaling was enhanced if SMAD3 could not be phosphorylated on Ser213 in the linker region and the inhibition by IL-1β was less if the SMAD3 linker could not be phosphorylated at Ser204. Our study shows evidence that inflammation inhibits SMAD2/3 signaling in chondrocytes via SMAD linker (de)-phosphorylation. The involvement of linker region modifications may represent a new therapeutic target for OA.
3
Thiriet, C., and J. J. Hayes. "Assembly into chromatin and subtype-specific transcriptional effects of exogenous linker histones directly introduced into a living Physarum cell." Journal of Cell Science 114, no. 5 (March 1, 2001): 965–73. http://dx.doi.org/10.1242/jcs.114.5.965.
Анотація:
The apparent diversity of linker histone subtypes may be related to their specific roles in defining functional states of chromatin in vivo. We have developed a novel method to study constitutive peptides throughout the cell cycle and have demonstrated that an exogenous linker histone could be introduced into a living cell of the slime mold Physarum polycephalum. Here, we have used this method to assess the functional differences between three somatic linker histone subtypes in vivo, and to demonstrate the general applicability of this method. Exogenous linker histone proteins H1 degrees, H5 and H1 were directly absorbed into living cell segments of the naturally synchronous Physarum macroplasmodia at precise cell cycle stages. Fluorescence microscopy, native nucleoprotein gels and immunoblotting of nuclei and chromatin with subtype-specific antibodies revealed that exogenous linker histones were efficiently transported into nuclei and were integrated into chromatin. The immunoreactivity of a preparation of anti-H1 degrees antibodies that are blocked from binding to specific H1 degrees epitopes in native chromatin indicates that the exogenous linker histones were similarly associated into Physarum chromatin. Interestingly, linker histones were found to be less stably associated with Physarum chromatin during S-phase than during G(2)-phase. Furthermore, we show that exogenous linker histones incorporated in early G(2)-phase inhibited transcription and that the level of inhibition correlates with the apparent role of the linker histone subtype in regulating transcription in cells where it normally occurs.
4
BLACK, Gary W., Jane E. RIXON, Jonathan H. CLARKE, Geoffrey P. HAZLEWOOD, Michael K. THEODOROU, Philip MORRIS, and Harry J. GILBERT. "Evidence that linker sequences and cellulose-binding domains enhance the activity of hemicellulases against complex substrates." Biochemical Journal 319, no. 2 (October 15, 1996): 515–20. http://dx.doi.org/10.1042/bj3190515.
Анотація:
Xylanase A (XYLA) and arabinofuranosidase C (XYLC) from Pseudomonas fluorescens subsp. cellulosa are modular enzymes consisting of discrete cellulose-binding domains (CBDs) and catalytic domains joined by serine-rich linker sequences. To evaluate the role of the CBDs and interdomain regions, the capacity of full-length and truncated derivatives of the two enzymes, lacking either the linker sequences or CBDs, to hydrolyse a range of substrates, and bind to cellulose, was determined. Removal of the CBDs did not affect either the activity of XYLA or XYLC against soluble arabinoxylan. Similarly, deletion of the linker sequences did not alter the affinity of the enzymes for cellulose or their activity against soluble substrates, even when bound to cellulose via the CBDs. Truncated derivatives of XYLA lacking either the linker sequences or the CBD were less active against xylan contained in cellulose-hemicellulose complexes, compared with the full-length xylanase. Similarly, removal of the CBD from XYLC diminished the activity of the enzyme (XYLC´´´) against plant-cell-wall material containing highly substituted arabinoxylan. The role of CBDs and linker sequences in the catalytic activity of hemicellulases against the plant cell wall is discussed.
5
Mathur, Rajesh, Jie Zheng, Yangyang Yan, and Fred J. Sigworth. "Role of the S3-S4 Linker in Shaker Potassium Channel Activation." Journal of General Physiology 109, no. 2 (February 1, 1997): 191–99. http://dx.doi.org/10.1085/jgp.109.2.191.
Анотація:
Structural models of voltage-gated channels suggest that flexibility of the S3-S4 linker region may be important in allowing the S4 region to undergo large conformational changes in its putative voltage-sensing function. We report here the initial characterization of 18 mutations in the S3-S4 linker of the Shaker channel, including deletions, insertions, charge changes, substitution of prolines, and chimeras replacing the 25-residue Shaker linker with 7- or 9-residue sequences from Shab, Shaw, or Shal. As measured in Xenopus oocytes with a two-microelectrode voltage clamp, each mutant construct yielded robust currents. Changes in the voltage dependence of activation were small, with activation voltage shifts of 13 mV or less. Substitution of linkers from the slowly activating Shab and Shaw channels resulted in a three- to fourfold slowing of activation and deactivation. It is concluded that the S3-S4 linker is unlikely to participate in a large conformational change during channel activation. The linker, which in some channel subfamilies has highly conserved sequences, may however be a determinant of activation kinetics in potassium channels, as previously has been suggested in the case of calcium channels.
6
Tomar, Rachana, Pankaj Sharma, Ankit Srivastava, Saurabh Bansal, Ashish, and Bishwajit Kundu. "Structural and functional insights into an archaealL-asparaginase obtained through the linker-less assembly of constituent domains." Acta Crystallographica Section D Biological Crystallography 70, no. 12 (November 22, 2014): 3187–97. http://dx.doi.org/10.1107/s1399004714023414.
Анотація:
Covalent linkers bridging the domains of multidomain proteins are considered to be crucial for assembly and function. In this report, an exception in which the linker of a two-domain dimeric L-asparaginase fromPyrococcus furiosus(PfA) was found to be dispensable is presented. Domains of this enzyme assembled without the linker into a conjoined tetrameric form that exhibited higher activity than the parent enzyme. The global shape and quaternary structure of the conjoined PfA were also similar to the wild-type PfA, as observed by their solution scattering profiles and X-ray crystallographic data. Comparison of the crystal structures of substrate-bound and unbound enzymes revealed an altogether new active-site composition and mechanism of action. Thus, conjoined PfA is presented as a unique enzyme obtained through noncovalent, linker-less assembly of constituent domains that is stable enough to function efficiently at elevated temperatures.
7
Al-Kutubi, Hanan, Alla Dikhtiarenko, Hamid Reza Zafarani, Ernst J. R. Sudhölter, Jorge Gascon, and Liza Rassaei. "Facile formation of ZIF-8 thin films on ZnO nanorods." CrystEngComm 17, no. 29 (2015): 5360–64. http://dx.doi.org/10.1039/c5ce00590f.
8
Shi, Fei, Song Qin, and Yin-Chu Wang. "The Coevolution of Phycobilisomes: Molecular Structure Adapting to Functional Evolution." Comparative and Functional Genomics 2011 (2011): 1–9. http://dx.doi.org/10.1155/2011/230236.
Анотація:
Phycobilisome is the major light-harvesting complex in cyanobacteria and red alga. It consists of phycobiliproteins and their associated linker peptides which play key role in absorption and unidirectional transfer of light energy and the stability of the whole complex system, respectively. Former researches on the evolution among PBPs and linker peptides had mainly focused on the phylogenetic analysis and selective evolution. Coevolution is the change that the conformation of one residue is interrupted by mutation and a compensatory change selected for in its interacting partner. Here, coevolutionary analysis of allophycocyanin, phycocyanin, and phycoerythrin and covariation analysis of linker peptides were performed. Coevolution analyses reveal that these sites are significantly correlated, showing strong evidence of the functional and structural importance of interactions among these residues. According to interprotein coevolution analysis, less interaction was found between PBPs and linker peptides. Our results also revealed the correlations between the coevolution and adaptive selection in PBS were not directly related, but probably demonstrated by the sites coupled under physical-chemical interactions.
9
Bašić, Ivana, and Irena Zovko Dinković. "Sintaktički, značenjski i uporabni status složenog veznika kao i." Jezikoslovlje 23, no. 2 (January 11, 2023): 281–99. http://dx.doi.org/10.29162/jez.2022.11.
Анотація:
This paper examines coordinated structures introduced by means of the multi-word linker kao i, which can link syntactic units ranging from phrases, clause constituents and clauses to sentences and parts of discourse. We first discuss the coordinating properties of the linker – structural independence, order of conjoining, concord – as well as its usage and interchangeability with other single and multi-word linkers and correlatives. Together with the structural properties, different meanings of the linker are discussed, namely, its core meaning of addition, complemented by the meanings of comparison or gradation. When used in its comparative meaning, the linker kao i links units in parenthetic coordination and is interchangeable with the preposition poput, while its usage in the meaning of gradation is similar to the usage of the correlative coordinator ne samo... nego/već. Although most of its syntactic properties would place the linker kao i in the category of coordinators with additive meaning, its meaning does not fully correspond with the meanings of single-word coordinators i and te, multi-word coordinators a i and ali i or the correlative i... i, with which it generally bears most resemblance and is largely interchangeable. The difference is that kao i exhibits some properties typical of either subordinated or juxtaposed structures, for example, a lower degree of conceptual distance and instability in terms of concord. To further investigate these findings, we compared the multi-word linker kao i to its corresponding linker in English, as well as, and concluded that in both languages these linkers are less prototypical additive coordinators that frequently express parenthetic (additional information) coordination of comparative or gradational nature.
10
Zhang, Shaodong, Ralph-Olivier Moussodia, Sabine Vértesy, Sabine André, Michael L. Klein, Hans-Joachim Gabius, and Virgil Percec. "Unraveling functional significance of natural variations of a human galectin by glycodendrimersomes with programmable glycan surface." Proceedings of the National Academy of Sciences 112, no. 18 (April 20, 2015): 5585–90. http://dx.doi.org/10.1073/pnas.1506220112.
Анотація:
Surface-presented glycans (complex carbohydrates) are docking sites for adhesion/growth-regulatory galectins within cell–cell/matrix interactions. Alteration of the linker length in human galectin-8 and single-site mutation (F19Y) are used herein to illustrate the potential of glycodendrimersomes with programmable glycan displays as a model system to reveal the functional impact of natural sequence variations in trans recognition. Extension of the linker length slightly reduces lectin capacity as agglutinin and slows down aggregate formation at low ligand surface density. The mutant protein is considerably less active as agglutinin and less sensitive to low-level ligand presentation. The present results suggest that mimicking glycan complexity and microdomain occurrence on the glycodendrimersome surface can provide key insights into mechanisms to accomplish natural selectivity and specificity of lectins in structural and topological terms.
11
Chakafana, Zininga, and Shonhai. "The Link That Binds: The Linker of Hsp70 as a Helm of the Protein’s Function." Biomolecules 9, no. 10 (September 27, 2019): 543. http://dx.doi.org/10.3390/biom9100543.
Анотація:
The heat shock 70 (Hsp70) family of molecular chaperones plays a central role in maintaining cellular proteostasis. Structurally, Hsp70s are composed of an N-terminal nucleotide binding domain (NBD) which exhibits ATPase activity, and a C-terminal substrate binding domain (SBD). The binding of ATP at the NBD and its subsequent hydrolysis influences the substrate binding affinity of the SBD through allostery. Similarly, peptide binding at the C-terminal SBD stimulates ATP hydrolysis by the N-terminal NBD. Interdomain communication between the NBD and SBD is facilitated by a conserved linker segment. Hsp70s form two main subgroups. Canonical Hsp70 members generally suppress protein aggregation and are also capable of refolding misfolded proteins. Hsp110 members are characterized by an extended lid segment and their function tends to be largely restricted to suppression of protein aggregation. In addition, the latter serve as nucleotide exchange factors (NEFs) of canonical Hsp70s. The linker of the Hsp110 family is less conserved compared to that of the canonical Hsp70 group. In addition, the linker plays a crucial role in defining the functional features of these two groups of Hsp70. Generally, the linker of Hsp70 is quite small and varies in size from seven to thirteen residues. Due to its small size, any sequence variation that Hsp70 exhibits in this motif has a major and unique influence on the function of the protein. Based on sequence data, we observed that canonical Hsp70s possess a linker that is distinct from similar segments present in Hsp110 proteins. In addition, Hsp110 linker motifs from various genera are distinct suggesting that their unique features regulate the flexibility with which the NBD and SBD of these proteins communicate via allostery. The Hsp70 linker modulates various structure-function features of Hsp70 such as its global conformation, affinity for peptide substrate and interaction with co-chaperones. The current review discusses how the unique features of the Hsp70 linker accounts for the functional specialization of this group of molecular chaperones.
12
Ma, Yanhong, and Xin Zhang. "Structure Tuning of Hafnium Metal–Organic Frameworks through a Mixed Solvent Approach." Crystals 12, no. 6 (May 29, 2022): 785. http://dx.doi.org/10.3390/cryst12060785.
Анотація:
The recent development of water-stable metal–organic frameworks (MOFs) has significantly broadened the application scope of this emerging type of porous material. Structure tuning of hafnium MOFs is less studied compared with zirconium MOFs. In this work, we report the synthesis of a mesoporous hafnium MOF, csq-MOF-1, through finely tuning the solvent mixture ratio. The successful synthesis of csq-MOF-1 also relies on the linker flexibility as linker bending and a symmetry decrease were observed in this framework as compared to its structural isomer NPF-300 (Hf). The mesoporous feature and permanent porosity were determined by the N2 adsorption at 77 K. Such a hierarchical pore feature is expected to enable a variety of applications through encapsulation of large functional molecules. The synthetic strategy of utilizing a mixed solvent and flexible linker is expected to inspire the development of new hafnium MOFs with diverse topological structures.
13
Ayoub, Ghada, Mihails Arhangelskis, Xuan Zhang, Florencia Son, Timur Islamoglu, Tomislav Friščić, and Omar K. Farha. "Air oxidation of sulfur mustard gas simulants using a pyrene-based metal–organic framework photocatalyst." Beilstein Journal of Nanotechnology 10 (December 9, 2019): 2422–27. http://dx.doi.org/10.3762/bjnano.10.232.
Анотація:
We demonstrate a microporous metal–organic framework NU-400 based on a 2,7-disubstituted pyrene linker as a highly efficient photosensitizer for generating singlet oxygen and subsequent oxidative degradation of chemical warfare agents (CWAs). The high activity of NU-400 permits photocatalytic conversion of the 2-chloroethyl ethyl sulfide (CEES) mustard gas simulant into a benign sulfoxide derivative, in air, with less than 15 minutes’ half-life. This is a considerable improvement to NU-1000, based on a 1,3,6,8-tetrasubstituted pyrene unit, demonstrating how variation of the substitution pattern of a metal–organic framework linker permits modification of its photoactive behavior.
14
Xue, Jie, Bart Hoorelbeke, Ioannis Kagiampakis, Borries Demeler, Jan Balzarini, and Patricia J. LiWang. "The Griffithsin Dimer Is Required for High-Potency Inhibition of HIV-1: Evidence for Manipulation of the Structure of gp120 as Part of the Griffithsin Dimer Mechanism." Antimicrobial Agents and Chemotherapy 57, no. 8 (June 10, 2013): 3976–89. http://dx.doi.org/10.1128/aac.00332-13.
Анотація:
ABSTRACTGriffithsin (Grft) is a protein lectin derived from red algae that tightly binds the HIV envelope protein gp120 and effectively inhibits virus infection. This inhibition is due to the binding by Grft of high-mannose saccharides on the surface of gp120. Grft has been shown to be a tight dimer, but the role of the dimer in Grft's anti-HIV function has not been fully explored. To investigate the role of the Grft dimer in anti-HIV function, an obligate dimer of Grft was designed by expressing the protein with a peptide linker between the two subunits. This “Grft-linker-Grft” is a folded protein dimer, apparently nearly identical in structural properties to the wild-type protein. A “one-armed” obligate dimer was also designed (Grft-linker-Grft OneArm), with each of the three carbohydrate binding sites of one subunit mutated while the other subunit remained intact. While both constructed dimers retained the ability to bind gp120 and the viral surface, Grft-linker-Grft OneArm was 84- to 1,010-fold less able to inhibit HIV than wild-type Grft, while Grft-linker-Grft had near-wild-type antiviral potency. Furthermore, while the wild-type protein demonstrated the ability to alter the structure of gp120 by exposing the CD4 binding site, Grft-linker-Grft OneArm largely lost this ability. In experiments to investigate gp120 shedding, it was found that Grft has different effects on gp120 shedding for strains from subtype B and subtype C, and this might correlate with Grft function. Evidence is provided that the dimer form of Grft is critical to the function of this protein in HIV inhibition.
15
Li, Yong, Tomoki Kimura, John H. Laity, and Glen K. Andrews. "The Zinc-Sensing Mechanism of Mouse MTF-1 Involves Linker Peptides between the Zinc Fingers." Molecular and Cellular Biology 26, no. 15 (August 1, 2006): 5580–87. http://dx.doi.org/10.1128/mcb.00471-06.
Анотація:
ABSTRACT Mouse metal response element-binding transcription factor-1 (MTF-1) regulates the transcription of genes in response to a variety of stimuli, including exposure to zinc or cadmium, hypoxia, and oxidative stress. Each of these stresses may increase labile cellular zinc, leading to nuclear translocation, DNA binding, and transcriptional activation of metallothionein genes (MT genes) by MTF-1. Several lines of evidence suggest that the highly conserved six-zinc finger DNA-binding domain of MTF-1 also functions as a zinc-sensing domain. In this study, we investigated the potential role of the peptide linkers connecting the four N-terminal zinc fingers of MTF-1 in their zinc-sensing function. Each of these three linkers is unique, completely conserved among all known vertebrate MTF-1 orthologs, and different from the canonical Cys2His2 zinc finger TGEKP linker sequence. Replacing the RGEYT linker between zinc fingers 1 and 2 with TGEKP abolished the zinc-sensing function of MTF-1, resulting in constitutive DNA binding, nuclear translocation, and transcriptional activation of the MT-I gene. In contrast, swapping the TKEKP linker between fingers 2 and 3 with TGEKP had little effect on the metal-sensing functions of MTF-1, whereas swapping the canonical linker for the shorter TGKT linker between fingers 3 and 4 rendered MTF-1 less sensitive to zinc-dependent activation both in vivo and in vitro. These observations suggest a mechanism by which physiological concentrations of accessible cellular zinc affect MTF-1 activity. Zinc may modulate highly specific, linker-mediated zinc finger interactions in MTF-1, thus affecting its zinc- and DNA-binding activities, resulting in translocation to the nucleus and binding to the MT-I gene promoter.
16
Bodedla, Govardhana Babu, Geliang Tang, Jianzhang Zhao, and Xunjin Zhu. "A thiophene bridged naphthalimide–porphyrin complex with enhanced activity and stability in photocatalytic H2 evolution." Sustainable Energy & Fuels 4, no. 6 (2020): 2675–79. http://dx.doi.org/10.1039/d0se00356e.
Анотація:
More efficient intramolecular energy transfer in the naphthalimide–porphyrin complex, ZnT(p-NI)TP, is accomplished by an electron rich coplanar thiophene π-linkage compared to the analogous porphyrin ZnT(p-NI)PP bearing a less coplanar phenylene π-linker.
17
Ehrlicher, Allen J., Ramaswamy Krishnan, Ming Guo, Cécile M. Bidan, David A. Weitz, and Martin R. Pollak. "Alpha-actinin binding kinetics modulate cellular dynamics and force generation." Proceedings of the National Academy of Sciences 112, no. 21 (April 27, 2015): 6619–24. http://dx.doi.org/10.1073/pnas.1505652112.
Анотація:
The actin cytoskeleton is a key element of cell structure and movement whose properties are determined by a host of accessory proteins. Actin cross-linking proteins create a connected network from individual actin filaments, and though the mechanical effects of cross-linker binding affinity on actin networks have been investigated in reconstituted systems, their impact on cellular forces is unknown. Here we show that the binding affinity of the actin cross-linker α-actinin 4 (ACTN4) in cells modulates cytoplasmic mobility, cellular movement, and traction forces. Using fluorescence recovery after photobleaching, we show that an ACTN4 mutation that causes human kidney disease roughly triples the wild-type binding affinity of ACTN4 to F-actin in cells, increasing the dissociation time from 29 ± 13 to 86 ± 29 s. This increased affinity creates a less dynamic cytoplasm, as demonstrated by reduced intracellular microsphere movement, and an approximate halving of cell speed. Surprisingly, these less motile cells generate larger forces. Using traction force microscopy, we show that increased binding affinity of ACTN4 increases the average contractile stress (from 1.8 ± 0.7 to 4.7 ± 0.5 kPa), and the average strain energy (0.4 ± 0.2 to 2.1 ± 0.4 pJ). We speculate that these changes may be explained by an increased solid-like nature of the cytoskeleton, where myosin activity is more partitioned into tension and less is dissipated through filament sliding. These findings demonstrate the impact of cross-linker point mutations on cell dynamics and forces, and suggest mechanisms by which such physical defects lead to human disease.
18
Chen, Kui, Tian Yun Zhang, and Xiao Ping Zheng. "Preparation and Water-Absorbing Capacity of Poly(Acrylic Acid)/Montmorillonite Composites." Applied Mechanics and Materials 404 (September 2013): 393–97. http://dx.doi.org/10.4028/www.scientific.net/amm.404.393.
Анотація:
Poly (acrylic acid)/montmorillonite (PAA/MMT) superabsorbent composites was synthesized by high temperature rapid-induced solvent polymerization reaction. The structure of this composites was investigated by XRD. The relationship between reaction condition and water-absorbing capacity of this composites was researched. The result shows that, when montmorillonite content is less than 5 wt%, PAA/MMT composites is nanophase materials. With the increase of cross linker, neutralization degree of acrylic acid, or montmorillonite content, water-absorbing capacity of prepared composites first rises then decreases. When cross linker content is 0.225 wt%, neutralization degree is 70%, and montmorillonite content is 5 wt%, PAA/MMT composites possess microporous structure and its water-absorbing capacity is 511 times of the solid weight itself.
19
Herlan, Claudine Nicole, Katharina Sommer, Patrick Weis, Martin Nieger, and Stefan Bräse. "Structural Diversity of Peptoids: Tube-Like Structures of Macrocycles." Molecules 26, no. 1 (December 31, 2020): 150. http://dx.doi.org/10.3390/molecules26010150.
Анотація:
Peptoids, or poly-N-substituted glycines, are characterised by broad structural diversity. Compared to peptides, they are less restricted in rotation and lack backbone-derived H bonding. Nevertheless, certain side chains force the peptoid backbone into distinct conformations. Designable secondary structures like helices or nanosheets arise from this knowledge. Herein, we report the copper-catalysed alkyne-azide cycloaddition (CuAAC) of macrocycles to form innovative tube-like tricyclic peptoids, giving access to host–guest chemistry or storage applications. Different linker systems make the single tubes tuneable in size and enable modifications within the gap. An azobenzene linker, which is reversibly switchable in conformation, was successfully incorporated and allowed for light-triggered changes of the entire tricyclic structure.
20
Subramanian Manimekalai, Malathy Sony, Wuan Geok Saw, Ankita Pan, Ardina Grüber, and Gerhard Grüber. "Identification of the critical linker residues conferring differences in the compactness of NS5 fromDengue virusserotype 4 and NS5 fromDengue virusserotypes 1–3." Acta Crystallographica Section D Structural Biology 72, no. 6 (May 25, 2016): 795–807. http://dx.doi.org/10.1107/s2059798316006665.
Анотація:
Dengue virus(DENV) nonstructural protein 5 (NS5) consists of a methyltransferase (MTase) domain and an RNA-dependent RNA polymerase (RdRp) domain. The cross-talk between these domains occursviaa ten-residue linker. Recent solution studies of DENV NS5 from all four serotypes (DENV-1 to DENV-4) showed that NS5 adopts multiple conformations owing to its flexible linker and that DENV-4 NS5 is more compact and less flexible compared with NS5 from DENV-1 to DENV-3 [Sawet al.(2015),Acta Cryst.D71, 2309–2327]. Here, using a variety of single, double, triple and quadruple mutants of DENV-4 NS5 combined with solution X-ray scattering studies, insight into the critical residues responsible for the differential flexibility of DENV-4 NS5 is presented. The DENV-4 NS5 mutants K271T and S266N/T267A as well as the deletion mutant ΔS266T267showed enlarged dimensions and flexibility similar to those of DENV-3 NS5. The data indicate that the residues Lys271, Ser266 and Thr267 are important for the compactness of DENV-4 NS5 and therefore may be critical for the regulation of virus replication. Furthermore, quantitative characterization of the flexibility of these DENV-4 NS5 linker mutants using the ensemble-optimization method revealed that these mutants possess a similar conformational distribution to DENV-3 NS5, confirming that these residues in the linker region cause the higher compactness of DENV-4 NS5.
21
Malaby, Heidi LH, Dominique V. Lessard, Christopher L. Berger, and Jason Stumpff. "KIF18A's neck linker permits navigation of microtubule-bound obstacles within the mitotic spindle." Life Science Alliance 2, no. 1 (January 17, 2019): e201800169. http://dx.doi.org/10.26508/lsa.201800169.
Анотація:
KIF18A (kinesin-8) is required for mammalian mitotic chromosome alignment. KIF18A confines chromosome movement to the mitotic spindle equator by accumulating at the plus-ends of kinetochore microtubule bundles (K-fibers), where it functions to suppress K-fiber dynamics. It is not understood how the motor accumulates at K-fiber plus-ends, a difficult feat requiring the motor to navigate protein dense microtubule tracks. Our data indicate that KIF18A's relatively long neck linker is required for the motor's accumulation at K-fiber plus-ends. Shorter neck linker (sNL) variants of KIF18A display a deficiency in accumulation at the ends of K-fibers at the center of the spindle. Depletion of K-fiber–binding proteins reduces the KIF18A sNL localization defect, whereas their overexpression reduces wild-type KIF18A's ability to accumulate on this same K-fiber subset. Furthermore, single-molecule assays indicate that KIF18A sNL motors are less proficient in navigating microtubules coated with microtubule-associated proteins. Taken together, these results support a model in which KIF18A's neck linker length permits efficient navigation of obstacles to reach K-fiber ends during mitosis.
22
Caffrey, Conor R., Dietmar Steverding, Ryan K. Swenerton, Ben Kelly, Deirdre Walshe, Anjan Debnath, Yuan-Min Zhou, et al. "Bis-Acridines as Lead Antiparasitic Agents: Structure-Activity Analysis of a Discrete Compound Library In Vitro." Antimicrobial Agents and Chemotherapy 51, no. 6 (March 19, 2007): 2164–72. http://dx.doi.org/10.1128/aac.01418-06.
Анотація:
ABSTRACT Parasitic diseases are of enormous public health significance in developing countries—a situation compounded by the toxicity of and resistance to many current chemotherapeutics. We investigated a focused library of 18 structurally diverse bis-acridine compounds for in vitro bioactivity against seven protozoan and one helminth parasite species and compared the bioactivities and the cytotoxicities of these compounds toward various mammalian cell lines. Structure-activity relationships demonstrated the influence of both the bis-acridine linker structure and the terminal acridine heterocycle on potency and cytotoxicity. The bioactivity of polyamine-linked acridines required a minimum linker length of approximately 10 Å. Increasing linker length resulted in bioactivity against most parasites but also cytotoxicity toward mammalian cells. N alkylation, but less so N acylation, of the polyamine linker ameliorated cytotoxicity while retaining bioactivity with 50% effective concentration (EC50) values similar to or better than those measured for standard drugs. Substitution of the polyamine for either an alkyl or a polyether linker maintained bioactivity and further alleviated cytotoxicity. Polyamine-linked compounds in which the terminal acridine heterocycle had been replaced with an aza-acridine also maintained acceptable therapeutic indices. The most potent compounds recorded low- to mid-nanomolar EC50 values against Plasmodium falciparum and Trypanosoma brucei; otherwise, low-micromolar potencies were measured. Importantly, the bioactivity of the library was independent of P. falciparum resistance to chloroquine. Compound bioactivity was a function of neither the potential to bis-intercalate DNA nor the inhibition of trypanothione reductase, an important drug target in trypanosomatid parasites. Our approach illustrates the usefulness of screening focused compound libraries against multiple parasite targets. Some of the bis-acridines identified here may represent useful starting points for further lead optimization.
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Tauber, Maria, Sarah Kreuz, Alexander Lemak, Papita Mandal, Zhadyra Yerkesh, Alaguraj Veluchamy, Bothayna Al-Gashgari, et al. "Alternative splicing and allosteric regulation modulate the chromatin binding of UHRF1." Nucleic Acids Research 48, no. 14 (July 1, 2020): 7728–47. http://dx.doi.org/10.1093/nar/gkaa520.
Анотація:
Abstract UHRF1 is an important epigenetic regulator associated with apoptosis and tumour development. It is a multidomain protein that integrates readout of different histone modification states and DNA methylation with enzymatic histone ubiquitylation activity. Emerging evidence indicates that the chromatin-binding and enzymatic modules of UHRF1 do not act in isolation but interplay in a coordinated and regulated manner. Here, we compared two splicing variants (V1, V2) of murine UHRF1 (mUHRF1) with human UHRF1 (hUHRF1). We show that insertion of nine amino acids in a linker region connecting the different TTD and PHD histone modification-binding domains causes distinct H3K9me3-binding behaviour of mUHRF1 V1. Structural analysis suggests that in mUHRF1 V1, in contrast to V2 and hUHRF1, the linker is anchored in a surface groove of the TTD domain, resulting in creation of a coupled TTD-PHD module. This establishes multivalent, synergistic H3-tail binding causing distinct cellular localization and enhanced H3K9me3-nucleosome ubiquitylation activity. In contrast to hUHRF1, H3K9me3-binding of the murine proteins is not allosterically regulated by phosphatidylinositol 5-phosphate that interacts with a separate less-conserved polybasic linker region of the protein. Our results highlight the importance of flexible linkers in regulating multidomain chromatin binding proteins and point to divergent evolution of their regulation.
24
Cai, Jiaqiang, Shuai Song, Qing Zong, Qigang Liu, and Jian Xu. "Abstract 596: Development and assessment of a novel tumor microenvironment activable linker (TMALIN) ADC platform for solid tumor treatments." Cancer Research 83, no. 7_Supplement (April 4, 2023): 596. http://dx.doi.org/10.1158/1538-7445.am2023-596.
Анотація:
Abstract Antibody-drug conjugates (ADC) are one of the fastest growing anticancer drugs, which bring cytotoxic drugs into tumors while avoiding high systemic toxicities. To date, all commercial ADCs use intracellular lysosomal cleavage mechanisms for payload release to kill tumor cells which is often limited by the low tumor antigen expression. To this end, a novel systemically stable and extracellular tumor microenvironment activable linker-payload technology platform has been developed. Preclinical assessments demonstrated that the highly hydrophilic linker-payload, which showed limited impact on the hydrophilicity of antibody, prolonged the retention time in vivo and eventually enhanced the in vivo potency of ADC. The linker-payload is stable with less than 2% payload drop-off after 28-day incubation in plasma under physiological conditions in vitro. The high stability was also illustrated by GLP cynomolgus monkey studies and preliminary clinical trial data, with the overlap of ADC and TAb PK profile. Furthermore, a battery in vitro and in vivo cell line-derived xenograft (CDX) mouse model studies showed the linker-payload is stable in normal tissues but efficiently releases the payload in tumor tissues. The ADCs using TMALIN platform elucidated significant anti-tumor activity advantages when compared with those marketed ADCs targeting the same antigen, besides showing an acceptable safety profile in pivotal NHP studies without lung/liver/kidney toxicities. In summary, the TMALIN platform addresses the unmet need of ADCs by releasing the payload extracellularly in tumors and tumor microenvironments on top of the known intracellular lysosomal cleavage mechanisms. Continued clinical validation work is underway for several pipeline candidates as well as investigation into other target areas. Citation Format: Jiaqiang Cai, Shuai Song, Qing Zong, Qigang Liu, Jian Xu. Development and assessment of a novel tumor microenvironment activable linker (TMALIN) ADC platform for solid tumor treatments [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 596.
25
Xiao, Liang, Wei Lian, Shuai Song, Qigang Liu, Qing Zong, Sasha Stann, Jiaqiang Cai, and Tongtong Xue. "Abstract 2615: Preclinical development of a next generation antibody drug conjugate (ADC) targeting cMET for treatment of solid tumors." Cancer Research 84, no. 6_Supplement (March 22, 2024): 2615. http://dx.doi.org/10.1158/1538-7445.am2024-2615.
Анотація:
Abstract cMET (mesenchymal-epithelial transition factor), which belongs to the MET family, is a type of receptor tyrosine kinase that is expressed on the surfaces of various epithelial cells. The elevation of cMET can promote the development and progression of multiple cancers. cMET- ADCs have shown promising clinical activity with highest cMET levels, indicating tumor cMET levels may be limited for efficacy. YL211, a novel cMET-ADC was developed by leveraging on MediLink’s tumor microenvironment activable linker-payload platform (TMALIN platform), which could release the payload both in the tumor cell and in the tumor microenvironment. YL211 is comprised of an anti-cMET humanized monoclonal antibody conjugated to a novel topoisomerase 1 inhibitor via a protease-cleavable linker. The novel linker-payload and site-specific conjugation of YL211 results in a homogeneous product with a DAR (Drug-to-Antibody Ratio) of 8. Furthermore, the advancement in linker-payload design has facilitated the development of more hydrophilic ADCs, which exhibit minimal impact on the antibody's characteristics while being less prone to aggregation and showcasing lower systematic clearance. Along with release of the payload in the tumor microenvironment extracellularly, upon binding to cMET on tumor cell surfaces, the antigen-ADC complexes are internalized to lysosomal vesicles and subsequently release the toxic payload. The cytotoxic features drive cell cycle arrest, apoptosis, elevation of PARP/caspase 7 expression, as well as cell death and bystander effect. These findings translated in vivo where YL211 showed superior efficacy in causing tumor regressions and good tolerability in both cell lines and patient-derived xenograft (CDX and PDX) mouse models with both low to high cMET expression levels (H358, CR5088, ect.). The in vivo pharmacokinetics in monkeys showed that YL211 is highly stable with less than 0.1% (molar ratio) payload released in circulation. GLP safety evaluations demonstrated good safety profiles and no off-target toxicity in monkeys. These non-clinical data suggest the stability of the linker in circulation as well as efficient release of the payload in tumors with improved therapeutic window. Taken together, preclinical data suggest that YL211 could be a promising treatment strategy for cMET positive cancer patients. Citation Format: Liang Xiao, Wei Lian, Shuai Song, Qigang Liu, Qing Zong, Sasha Stann, Jiaqiang Cai, Tongtong Xue. Preclinical development of a next generation antibody drug conjugate (ADC) targeting cMET for treatment of solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2615.
26
Teng, Jinfeng, Stephen H. Loukin, Andriy Anishkin, and Ching Kung. "A competing hydrophobic tug on L596 to the membrane core unlatches S4–S5 linker elbow from TRP helix and allows TRPV4 channel to open." Proceedings of the National Academy of Sciences 113, no. 42 (October 3, 2016): 11847–52. http://dx.doi.org/10.1073/pnas.1613523113.
Анотація:
We have some generalized physical understanding of how ion channels interact with surrounding lipids but few detailed descriptions on how interactions of particular amino acids with contacting lipids may regulate gating. Here we discovered a structure-specific interaction between an amino acid and inner-leaflet lipid that governs the gating transformations of TRPV4 (transient receptor potential vanilloid type 4). Many cation channels use a S4–S5 linker to transmit stimuli to the gate. At the start of TRPV4’s linker helix is leucine 596. A hydrogen bond between the indole of W733 of the TRP helix and the backbone oxygen of L596 secures the helix/linker contact, which acts as a latch maintaining channel closure. The modeled side chain of L596 interacts with the inner lipid leaflet near the polar–nonpolar interface in our model—an interaction that we explored by mutagenesis. We examined the outward currents of TRPV4-expressing Xenopus oocyte upon depolarizations as well as phenotypes of expressing yeast cells. Making this residue less hydrophobic (L596A/G/W/Q/K) reduces open probability [Po; loss-of-function (LOF)], likely due to altered interactions at the polar–nonpolar interface. L596I raises Po [gain-of-function (GOF)], apparently by placing its methyl group further inward and receiving stronger water repulsion. Molecular dynamics simulations showed that the distance between the levels of α-carbons of H-bonded residues L596 and W733 is shortened in the LOFs and lengthened in the GOFs, strengthening or weakening the linker/TRP helix latch, respectively. These results highlight that L596 lipid attraction counteracts the latch bond in a tug-of-war to tune the Po of TRPV4.
27
KIM, BYUNGCHUL, XIAO-LI SU, and YANBIN LI. "Evaluation of a Capillary Immunoassay System for Detection of Salmonella Typhimurium in Poultry Products." Journal of Food Protection 68, no. 9 (September 1, 2005): 1799–803. http://dx.doi.org/10.4315/0362-028x-68.9.1799.
Анотація:
A capillary immunoassay system was constructed and optimized for detection of Salmonella Typhimurium. The system consisted of a capillary bioseparator-bioreactor and a flow-injection electrochemical detector. Three methods were compared for immobilizing antibodies on the inner surface of silica capillary columns; these methods were based on the use of a homobifunctional cross-linker glutaraldehyde, a heterobifunctional cross-linker N-succinimidyl-4-maleimidobutyrate, and biotin-streptavidin chemistry, respectively. The glutaraldehyde method gave the best reproducibility with a relative standard deviation of 1 to 6% for detection of Salmonella Typhimurium. The optimized immunoassay system could detect Salmonella Typhimurium in chicken breast and ground turkey meats with a detection limit of 2.4 × 103 and 2.4 × 104 CFU/ml, respectively. The total detection time was less than 2.5 h without any preenrichment. When stored at 4°C, the immunocolumns could retain their activities for at least 3 months.
28
Panjarian, Shoghag, Shugui Chen, John Engen, and Thomas Smithgall. "Enhanced SH3:Linker Interaction Suppresses Activating Mutations of the c-Abl Protein-Tyrosine Kinase." Blood 116, no. 21 (November 19, 2010): 1208. http://dx.doi.org/10.1182/blood.v116.21.1208.1208.
Анотація:
Abstract Abstract 1208 Bcr-Abl, the chimeric protein-tyrosine kinase expressed as a result of the Philadelphia chromosome translocation, plays a pivotal role in the initiation and maintenance of chronic myelogenous leukemia (CML). Imatinib (Gleevec) is an ATP-competitive Bcr-Abl inhibitor that selectively kills Bcr-Abl+ CML cells. Despite its clinical success, imatinib is less effective in the advanced stages of CML due to the emergence of drug resistance caused by point mutations in the Abl kinase domain. Second generation Bcr-Abl inhibitors such as dasatinib and nilotinib are active against most imatinib-resistant forms of Bcr-Abl, with the exception of the T315I “gatekeeper” mutant. The Abl gatekeeper residue (Thr315) is located between the ATP-binding site and an adjacent hydrophobic pocket, and forms a key hydrogen bond with imatinib. Additionally, the T315I mutation produces a strong activating effect on the downregulated c-Abl “core,” consisting of the myristoylated N-terminal Ncap, tandem SH3 and SH2 regulatory domains, the SH2-kinase linker, which forms a polyproline type II helix for internal SH3 docking, and the tyrosine kinase domain. Using hydrogen-exchange mass spectrometry, we recently found that the T315I mutation not only induced conformational changes in the Abl kinase domain as expected, but also at a distance in the RT-loop of the SH3 domain. Such changes may allosterically contribute to kinase domain activation by disturbing the negative regulatory influence of SH3:linker interaction. Recently, a new class of allosteric Bcr-Abl inhibitors has been reported that targets the myristate-binding pocket of Abl, which localizes to C-lobe of the kinase domain and away from the active site. Together with our finding that the T315I mutation perturbs SH3:linker interaction, these inhibitors support the existence of an extensive network of allosteric interactions that work together to regulate Abl kinase activity. In this project, we investigated whether enhanced SH3:linker interaction can allosterically reverse the activating effects of the T315I imatinib resistance mutation as well as mutations of the N-terminal myristoylation site and myristic acid binding pocket. We created modified versions of Abl [High Affinity Linker proteins (HALs)] by mutating multiple residues within the SH2-kinase linker to proline, thereby enhancing the SH3 domain binding affinity. Using mammalian cell-based expression assays and immunoblotting with phosphospecific antibodies, we identified five of eleven Abl-HAL proteins that did not exhibit changes in basal kinase activity. The Abl-HAL protein with the greatest enhancement of SH3:linker interaction was then combined with the T315I mutation, a myristoylation-defective mutant, and a myristic acid binding pocket mutation. Remarkably, this HAL substitution completely reversed the activating effect of the myristic acid binding pocket mutation, while substantially suppressing the activity of Abl T315I and the myristoylation-defective mutant. These results indicate that stabilization of SH3:linker interaction allosterically represses Abl activation by a wide variety of mechanisms, and suggests a new approach to allosteric control of Bcr-Abl kinase activity. Disclosures: No relevant conflicts of interest to declare.
29
Prachařová, Jitka, Olga Nováková, Jana Kašpárková, Dan Gibson, and Viktor Brabec. "Toxicity in tumor cells, DNA binding mode, and resistance to decomposition by sulfur nucleophiles of new dinuclear bifunctional trans-PtII complexes containing long alkane linkers." Pure and Applied Chemistry 85, no. 2 (December 7, 2012): 343–54. http://dx.doi.org/10.1351/pac-con-12-07-08.
Анотація:
In an effort to design dinuclear PtII compounds that maintain the target (DNA) binding profile of the trans-oriented dinuclear bifunctional PtII complexes containing aliphatic linker chains but are less susceptible to metabolic decomposition, the new, long-chain dinuclear PtII complexes—[{trans-PtCl(dien)}2-μ-(CH2)n]2+ (n = 7,10,12, dien = diethylenetriamine)—were synthesized. The toxicity of these metallodrugs was examined in ovarian tumor cell lines. The results showed that the activity of these complexes increased with growing length of the linker; the activity of complex containing the longest linker (n = 12) was comparable with that of cis-diamminedichloridoplatinum(II) (cisplatin). This observation correlated with the results of DNA binding studies performed in cell-free media. The results of these studies demonstrated that the growing length of the aliphatic bridge promoted more distorting conformational alterations induced in DNA. Attention was also paid to the reactivity of {[Pt(dien)Cl]2-alkane} compounds with glutathione (GSH). The results of these experiments support the thesis that the dinuclear structure of {[Pt(dien)Cl]2-alkane} complexes remains stable in the presence of S-containing compounds without undergoing chemical degradation as previously observed for some di/trinuclear bifunctional PtII complexes. This enhanced stability represents a favorable property which may contribute to reduce side effects and increase therapeutic efficacy of the dinuclear {[Pt(dien)Cl]2-alkane} compounds.
30
Camacho Ramirez, Abygail, Miguel Melendez-Zamudio, Antonio Guerra Contreras, and Michael A. Brook. "Lysine-Based Silicone Surfactants." Sustainable Chemistry 4, no. 2 (May 4, 2023): 197–208. http://dx.doi.org/10.3390/suschem4020015.
Анотація:
Highly efficient silicone surfactants are typically based on polyether hydrophiles. As part of a program to increase the natural content of silicones, we describe the synthesis of silicone surfactants with amino acid hydrophiles (cysteine, arginine, and lysine). The compounds were prepared using a radial thiol–ene reaction with vinylsilicones for cysteine derivatives and a catalyst-free aza-Michael reaction with arginine and lysine. Short chain surfactants with silicone monomer:hydrophile ratios of 5:1 or less (e.g., telechelic silicones of lysine-linker-(Me2OSi)n-linker-lysine n = 10) were ineffective at stabilizing emulsions of silicone oil (D4): water. However, excellent surfactants were realized as the chain length (n) increased to 25 or 50, stabilizing water-in-oil emulsions with high water content (80% or 90%). The surfactants, especially the longer chain compounds, were stable against pH except <4 or >9 and survived freeze/thaw cycles. These surfactants contain 12–25% natural materials, improving their sustainability compared to those containing synthetic hydrophiles.
31
Routholla, Ganesh, Sravani Pulya, Tarun Patel, Sk Abdul Amin, Nilanjan Adhikari, Swati Biswas, Tarun Jha, and Balaram Ghosh. "Synthesis, biological evaluation, and molecular docking analysis of novel linker-less benzamide based potent and selective HDAC3 inhibitors." Bioorganic Chemistry 114 (September 2021): 105050. http://dx.doi.org/10.1016/j.bioorg.2021.105050.
32
Tomar, Rachana, Pankaj Sharma, Ankit Srivastava, Saurabh Bansal, Ashish, and Bishwajit Kundu. "Structural and functional insights into an archaealL-asparaginase obtained through the linker-less assembly of constituent domains. Corrigendum." Acta Crystallographica Section D Structural Biology 72, no. 1 (January 1, 2016): 180. http://dx.doi.org/10.1107/s205979831502361x.
33
Mishra, Rajnikant, Ivan P. Gorlov, Lian Y. Chao, Sanjaya Singh, and Grady F. Saunders. "PAX6, Paired Domain Influences Sequence Recognition by the Homeodomain." Journal of Biological Chemistry 277, no. 51 (October 17, 2002): 49488–94. http://dx.doi.org/10.1074/jbc.m206478200.
Анотація:
PAX6 functions as a transcription factor and has two DNA-binding domains, a paired domain (PD) and a homeodomain (HD), joined by a glycine-rich linker and followed by a proline-serine-threonine-rich (PST) transactivation region at the C terminus. The mechanism of PAX6 function is not clearly understood, and few target genes in vertebrates have been identified. In this report we described the functional analyses of patient missense mutations from the paired domain region of PAX6 and a paireddomain-less isoform (PD-less) of Pax6 that lacks the paired domain and part of the glycine-rich linker. The PD-less was expressed in the brain, eyes, and pancreas of mouse. The level of expression of this isoform was relatively higher in brain. The mutation sites PAX6-L46R and -C52R were located in the PD of PAX6 on either end of the 5a-polypeptide insert of the alternatively spliced form of PAX6, PAX6-5a. Another PAX6 mutant V53L described in this report was adjacent to C52R. We created corresponding mutations in PAX6 and PAX6-5a, and evaluated their transcriptional activation and DNA binding properties. The PD mutants of PAX6 (L46R, C52R, and V53L) exhibited lower transactivation activities and variable DNA binding ability than wild-type PAX6 with PD DNA-binding consensus sequences. The mutated amino acids containing PAX6-5a isoforms showed unexpected transactivation properties with a reporter containing HD DNA-binding sequences. PAX6-5a-C52R, and -V53L showed lower transactivation activities, but PAX6-5a-L46R had greater transactivation ability than PAX6-5a. The PD-less isoform of Pax6 lost its transactivational ability but could bind to the HD DNA-binding sequences. Functional analysis of the PD-less isoform of Pax6 as well as findings related to missense mutations in the PD suggest that the PD of PAX6 is required for HD function.
34
Nishi, Akari, Hikaru Matsui, Azumi Hirata, Atsushi Mukaiyama, Shun-ichi Tanaka, Takuya Yoshizawa, Hiroyoshi Matsumura, Ryota Nomura, Kazuhiko Nakano, and Kazufumi Takano. "Structure, Stability and Binding Properties of Collagen-Binding Domains from Streptococcus mutans." Chemistry 5, no. 3 (September 1, 2023): 1911–20. http://dx.doi.org/10.3390/chemistry5030130.
Анотація:
Collagen-binding proteins (CBP), Cnm and Cbm, from Streptococcus mutans are involved in infective endocarditis caused by S. mutans because of their collagen-binding ability. In this study, we focused on the collagen-binding domain (CBD), which is responsible for the collagen-binding ability of CBP, and analyzed its structure, binding activity, and stability using CBD domain variants. The CBD consists of the N1 domain, linker, N2 domain, and latch (N1-N2~) as predicted from the amino acid sequences. The crystal structure of the Cnm/CBD was determined at a 1.81 Å resolution. N1_linker_N2 forms a ring structure that can enfold collagen molecules, and the latch interacts with N1 to form a ring clasp. N1 and N2 have similar immunoglobulin folds. The collagen-binding activities of Cbm/CBD and its domain variants were examined using ELISA. N1-N2~ bound to collagen with KD = 2.8 μM, and the latch-deleted variant (N1-N2) showed weaker binding (KD = 28 μM). The linker-deleted variant (N1N2~) and single-domain variants (N1 and N2) showed no binding activity, whereas the domain-swapped variant (N2-N1~) showed binding ability, indicating that the two N-domains and the linker are important for collagen binding. Thermal denaturation experiments showed that N1-N2 was slightly less stable than N1-N2~, and that N2 was more stable than N1. The results of this study provide a basis for the development of CBD inhibitors and applied research utilizing their collagen-binding ability.
35
Rakhmetova, S. Yu, S. P. Radko, O. V. Gnedenko, N. V. Bodoev, A. S. Ivanov, and A. I. Archakov. "Photoaptamer heterodimeric constructs as a new approach to enhance the efficiency of formation of photocrosslinking with a target protein." Biomeditsinskaya Khimiya 56, no. 1 (January 2010): 72–81. http://dx.doi.org/10.18097/pbmc20105601072.
Анотація:
Using two DNA aptamers selectively recognizing anion-binding exosites 1 and 2 of thrombin as a model, it has been demonstrated that their conjugation by a poly-(dT)-linker (ranging from 5 to 65 nt in length) to produce aptamer heterodimeric constructs results into affinity enhancement. The apparent dissociation constant (Kdapp) measured at the optical biosensor Biacore-3000 for complexes of thrombin with the heterodimeric constructs reached minimum values (Kdapp = 0,2-0,4 nМ) which were approximately 30-fold less than for the complexes with the primary aptamers. A photoaptamer heterodimeric construct was designed connecting photoaptamer and aptamer sequences with the poly-(dT)-linker of 35 nt long. The photoaptamer used could form photo-induced cross-links with the exosite 2 of thrombin and the aptamer used could bind to the exosite 1. The measured value of Kdapp for the photoaptamer construct was approximately 40-fold less than that for the primary photoaptamer (5,3 and 190 nM, respectively). Upon exposure to the UV radiation at 308 nm of the equimolar mixtures of thrombin with the photoaptamer construct, the equal yield of the crosslinked complexes was observed at concentrations which were lower by two orders of magnitude than in the case of the primary photoaptamer. It was found that concurrently with crosslinking to thrombin a photo-induced inactivation of the photoaptamer occurs presumably due to formation of the intermolecular crosslinking.
36
Parseghian, Missag H., and Barbara A. Hamkalo. "A compendium of the histone H1 family of somatic subtypes: An elusive cast of characters and their characteristics." Biochemistry and Cell Biology 79, no. 3 (June 1, 2001): 289–304. http://dx.doi.org/10.1139/o01-099.
Анотація:
The last 35 years has seen a substantial amount of information collected about the somatic H1 subtypes, yet much of this work has been overshadowed by research into highly divergent isoforms of H1, such as H5. Reports from several laboratories in the past few years have begun to call into question some of the traditional views regarding the general function of linker histones and their heterogeneity. Hence, the impression in some circles is that less is known about these ubiquitous nuclear proteins as compared with the core histones. The goal of the following review is to acquaint the reader with the ubiquitous somatic H1s by categorizing them and their characteristics into several classes. The reasons for our current state of misunderstanding is put into a historical context along with recent controversies centering on the role of H1 in the nucleus. Finally, we propose a model that may explain the functional role of H1 heterogeneity in chromatin compaction.Key words: histone H1, linker histones, chromatin organization, chromatin compaction, heat shock.
37
Chun, Jong-Yoon, Kyoung-Joong Kim, In-Taek Hwang, Yun-Jee Kim, Dae-Hoon Lee, In-Kyoung Lee, and Jong-Kee Kim. "Dual priming oligonucleotide system for the multiplex detection of respiratory viruses and SNP genotyping of CYP2C19 gene." Nucleic Acids Research 35, no. 6 (February 7, 2007): e40-e40. http://dx.doi.org/10.1093/nar/gkm051.
Анотація:
Abstract Successful PCR starts with proper priming between an oligonucleotide primer and the template DNA. However, the inevitable risk of mismatched priming cannot be avoided in the currently used primer system, even though considerable time and effort are devoted to primer design and optimization of reaction conditions. Here, we report a novel dual priming oligonucleotide (DPO) which contains two separate priming regions joined by a polydeoxyinosine linker. The linker assumes a bubble-like structure which itself is not involved in priming, but rather delineates the boundary between the two parts of the primer. This structure results in two primer segments with distinct annealing properties: a longer 5′-segment that initiates stable priming, and a short 3′-segment that determines target-specific extension. This DPO-based system is a fundamental tool for blocking extension of non-specifically primed templates, and thereby generates consistently high PCR specificity even under less than optimal PCR conditions. The strength and utility of the DPO system are demonstrated here using multiplex PCR and SNP genotyping PCR.
38
Siddiqui, Tabrez J., Olga Vites, Alexander Stein, Rainer Heintzmann, Reinhard Jahn, and Dirk Fasshauer. "Determinants of Synaptobrevin Regulation in Membranes." Molecular Biology of the Cell 18, no. 6 (June 2007): 2037–46. http://dx.doi.org/10.1091/mbc.e07-01-0049.
Анотація:
Neuronal exocytosis is driven by the formation of SNARE complexes between synaptobrevin 2 on synaptic vesicles and SNAP-25/syntaxin 1 on the plasma membrane. It has remained controversial, however, whether SNAREs are constitutively active or whether they are down-regulated until fusion is triggered. We now show that synaptobrevin in proteoliposomes as well as in purified synaptic vesicles is constitutively active. Potential regulators such as calmodulin or synaptophysin do not affect SNARE activity. Substitution or deletion of residues in the linker connecting the SNARE motif and transmembrane region did not alter the kinetics of SNARE complex assembly or of SNARE-mediated fusion of liposomes. Remarkably, deletion of C-terminal residues of the SNARE motif strongly reduced fusion activity, although the overall stability of the complexes was not affected. We conclude that although complete zippering of the SNARE complex is essential for membrane fusion, the structure of the adjacent linker domain is less critical, suggesting that complete SNARE complex assembly not only connects membranes but also drives fusion.
39
Suresh, J., R. Yuvakkumar, A. Joseph Nathanael, M. Sundrarajan, and Sun Ig Hong. "Antibacterial and Wash Durability Properties of Untreated and Treated Cotton Fabric Using MgO and NiO Nanoparticles." Applied Mechanics and Materials 508 (January 2014): 48–51. http://dx.doi.org/10.4028/www.scientific.net/amm.508.48.
Анотація:
We report an antibacterial and wash durability behaviour of MgO and NiO nanoparticles treated cotton fabric using sodium alginate as cross linker. The metal oxide nanoparticles treated cotton fabric using sodium alginate as a crosslinker was characterized employing SEM-EDX and their antibacterial activity was analyzed. The enhanced zone of inhibition and wash durability behaviour was observed for NiO nanoparticles treated fabric. However, MgO nanoparticles showed less significant antibacterial and wash durabilty activities when compared to NiO nanoparticles treated cotton fabrics.
40
MÉRÉ, Jocelyn, Anne CHAHINIAN, Sutherland K. MACIVER, Abdellatif FATTOUM, Nadir BETTACHE, Yves BENYAMIN, and Claude ROUSTAN. "Gelsolin binds to polyphosphoinositide-free lipid vesicles and simultaneously to actin microfilaments." Biochemical Journal 386, no. 1 (February 8, 2005): 47–56. http://dx.doi.org/10.1042/bj20041054.
Анотація:
Gelsolin is a calcium-, pH- and lipid-dependent actin filament severing/capping protein whose main function is to regulate the assembly state of the actin cytoskeleton. Gelsolin is associated with membranes in cells, and it is generally assumed that this interaction is mediated by PPIs (polyphosphoinositides), since an interaction with these lipids has been characterized in vitro. We demonstrate that non-PPI lipids also bind gelsolin, especially at low pH. The data suggest further that gelsolin becomes partially buried in the lipid bilayer under mildly acidic conditions, in a manner that is not dependent of the presence of PPIs. Our data also suggest that lipid binding involves a number of sites that are spread throughout the gelsolin molecule. Linker regions between gelsolin domains have been implicated by other work, notably the linker between G1 and G2 (gelsolin domains 1 and 2 respectively), and we postulate that the linker region between the N-terminal and C-terminal halves of gelsolin (between G3 and G4) is also involved in the interaction with lipids. This region is compatible with other studies in which additional binding sites have been located within G4–6. The lipid–gelsolin interactions reported in the present paper are not calcium-dependent, and are likely to involve significant conformational changes to the gelsolin molecule, as the chymotryptic digest pattern is altered by the presence of lipids under our conditions. We also report that vesicle-bound gelsolin is capable of binding to actin filaments, presumably through barbed end capping. Gelsolin bound to vesicles can nucleate actin assembly, but is less active in severing microfilaments.
41
Amer, Adel, Abdelrahman H. Hegazi, Mohammed Khalil Alshekh, Hany E. A. Ahmed, Saied M. Soliman, Antonin Maniquet, and Rona R. Ramsay. "Design, synthesis, molecular modelling and in vitro screening of monoamine oxidase inhibitory activities of novel quinazolyl hydrazine derivatives." Royal Society Open Science 7, no. 4 (April 2020): 200050. http://dx.doi.org/10.1098/rsos.200050.
Анотація:
A new series of N'-substituted benzylidene-2-(4-oxo-2-phenyl-1,4-dihydroquinazolin-3(2H)-yl)acetohydrazide ( 5a–5h ) has been synthesized, characterized by FT-IR, NMR spectroscopy and mass spectrometry and tested against human monoamine oxidase (MAO) A and B. Only (4-hydroxy-3-methoxybenzylidene) substituted compounds gave submicromolar inhibition of MAO-A and MAO-B. Changing the phenyl substituent to methyl on the unsaturated quinazoline ring ( 12a–12d ) decreased inhibition, but a less flexible linker ( 14a–14d ) resulted in selective micromolar inhibition of hMAO-B providing insight for ongoing design.
42
Yan, Jianghong, Fei-Fei Shang, An He, Shupeng Hu, Suxin Luo, and Yong Xia. "N-Glycosylation at Asn695 might suppress inducible nitric oxide synthase activity by disturbing electron transfer." Acta Biochimica et Biophysica Sinica 52, no. 12 (November 21, 2020): 1360–72. http://dx.doi.org/10.1093/abbs/gmaa132.
Анотація:
Abstract Inducible nitric oxide synthase (iNOS) plays critical roles in the inflammatory response and host defense. Previous research on iNOS regulation mainly focused on its gene expression level, and much less is known about the regulation of iNOS function by N-glycosylation. In this study, we report for the first time that iNOS is N-glycosylated in vitro and in vivo. Mass spectrometry studies identified Asn695 as an N-glycosylation site of murine iNOS. Mutating Asn695 to Gln695 yields an iNOS that exhibits greater enzyme activity. The essence of nitric oxide synthase catalytic reaction is electron transfer process, which involves a series of conformational changes, and the linker between the flavin mononucleotide-binding domain and the flavin adenine dinucleotide-binding domain plays vital roles in the conformational changes. Asn695 is part of the linker, so we speculated that attachment of N-glycan to the Asn695 residue might inhibit activity by disturbing electron transfer. Indeed, our NADPH consumption results demonstrated that N-glycosylated iNOS consumes NADPH more slowly. Taken together, our results indicate that iNOS is N-glycosylated at its Asn695 residue and N-glycosylation of Asn695 might suppress iNOS activity by disturbing electron transfer.
43
Viville, S., V. Jongeneel, W. Koch, R. Mantovani, C. Benoist, and D. Mathis. "The E alpha promoter: a linker-scanning analysis." Journal of Immunology 146, no. 9 (May 1, 1991): 3211–17. http://dx.doi.org/10.4049/jimmunol.146.9.3211.
Анотація:
Abstract To accurately delineate the DNA sequence elements involved in the transcriptional regulation of the murine MHC class II gene E alpha, we have constructed a set of "linker-scanning" mutants of the E alpha promoter region. These were made by the gapped heteroduplex technique and result in a set of 10-bp replacement mutations, covering the -206 to -6 stretch of the promoter. The effect of these mutations on transcriptional activity was evaluated in several systems, either by transfection into cultured cells or by in vitro transcription. The data points to the now classical X and Y boxes as the most important control elements, either for constitutive expression in B lymphoma cells, or for IFN-gamma-inducible expression in macrophages. Motifs upstream of the X box also play a role, but are somewhat less critical. Overall, we find no marked difference between regulatory strategies in B lymphomas or activated macrophages.
44
Kay, Emma, Rouven Stulz, Cécile Becquart, Jelena Lovric, Carolina Tängemo, Aurélien Thomen, Dženita Baždarević, et al. "NanoSIMS Imaging Reveals the Impact of Ligand-ASO Conjugate Stability on ASO Subcellular Distribution." Pharmaceutics 14, no. 2 (February 21, 2022): 463. http://dx.doi.org/10.3390/pharmaceutics14020463.
Анотація:
The delivery of antisense oligonucleotides (ASOs) to specific cell types via targeted endocytosis is challenging due to the low cell surface expression of target receptors and inefficient escape of ASOs from the endosomal pathway. Conjugating ASOs to glucagon-like peptide 1 (GLP1) leads to efficient target knockdown, specifically in pancreatic β-cells. It is presumed that ASOs dissociate from GLP1 intracellularly to enable an ASO interaction with its target RNA. It is unknown where or when this happens following GLP1-ASO binding to GLP1R and endocytosis. Here, we use correlative nanoscale secondary ion mass spectroscopy (NanoSIMS) and transmission electron microscopy to explore GLP1-ASO subcellular trafficking in GLP1R overexpressing HEK293 cells. We isotopically label both eGLP1 and ASO, which do not affect the eGLP1-ASO conjugate function. We found that the eGLP1 peptide and ASO are not detected at the same level in the same endosomes, within 30 min of GLP1R-HEK293 cell exposure to eGLP1-ASO. When we utilized different linker chemistry to stabilize the GLP1-ASO conjugate, we observed more ASO located with GLP1 compared to cell incubation with the less stable conjugate. Overall, our work suggests that the ASO separates from GLP1 relatively early in the endocytic pathway, and that linker chemistry might impact the GLP1-ASO function.
45
Zhang, Juan, Elsa Berenstein та Reuben P. Siraganian. "Phosphorylation of Tyr342 in the Linker Region of Syk Is Critical for FcεRI Signaling in Mast Cells". Molecular and Cellular Biology 22, № 23 (1 грудня 2002): 8144–54. http://dx.doi.org/10.1128/mcb.22.23.8144-8154.2002.
Анотація:
ABSTRACT The linker region of Syk and ZAP70 tyrosine kinases plays an important role in regulating their function. There are three conserved tyrosines in this linker region; Tyr317 of Syk and its equivalent residue in ZAP70 were previously shown to negatively regulate the function of Syk and ZAP70. Here we studied the roles of the other two tyrosines, Tyr342 and Tyr346 of Syk, in FcεRI-mediated signaling. Antigen stimulation resulted in Tyr342 phosphorylation in mast cells. Syk with Y342F mutation failed to reconstitute FcεRI-initiated histamine release. In the Syk Y342F-expressing cells there was dramatically impaired receptor-induced phosphorylation of multiple signaling molecules, including LAT, SLP-76, phospholipase C-γ2, but not Vav. Compared to wild-type Syk, Y342F Syk had decreased binding to phosphorylated immunoreceptor tyrosine-based activation motifs and reduced kinase activity. Surprisingly, mutation of Tyr346 had much less effect on FcεRI-dependent mast cell degranulation. An anti-Syk-phospho-346 tyrosine antibody indicated that antigen stimulation induced only a very minor increase in the phosphorylation of this tyrosine. Therefore, Tyr342, but not Tyr346, is critical for regulating Syk in mast cells and the function of these tyrosines in immune receptor signaling appears to be different from what has been previously reported for the equivalent residues of ZAP70.
46
Tsao, Kelvin K., Ann C. Lee, Karl É. Racine, and Jeffrey W. Keillor. "Site-Specific Fluorogenic Protein Labelling Agent for Bioconjugation." Biomolecules 10, no. 3 (February 28, 2020): 369. http://dx.doi.org/10.3390/biom10030369.
Анотація:
Many clinically relevant therapeutic agents are formed from the conjugation of small molecules to biomolecules through conjugating linkers. In this study, two novel conjugating linkers were prepared, comprising a central coumarin core, functionalized with a dimaleimide moiety at one end and a terminal alkyne at the other. In our first design, we developed a protein labelling method that site-specifically introduces an alkyne functional group to a dicysteine target peptide tag that was genetically fused to a protein of interest. This method allows for the subsequent attachment of azide-functionalized cargo in the facile synthesis of novel protein-cargo conjugates. However, the fluorogenic aspect of the reaction between the linker and the target peptide was less than we desired. To address this shortcoming, a second linker reagent was prepared. This new design also allowed for the site-specific introduction of an alkyne functional group onto the target peptide, but in a highly fluorogenic and rapid manner. The site-specific addition of an alkyne group to a protein of interest was thus monitored in situ by fluorescence increase, prior to the attachment of azide-functionalized cargo. Finally, we also demonstrated that the cargo can also be attached first, in an azide/alkyne cycloaddition reaction, prior to fluorogenic conjugation with the target peptide-fused protein.
47
Chen, Qianfa, and Ken Armstrong. "Characterization of a library from a single microdissected oat (Avena sativa L.) chromosome." Genome 38, no. 4 (August 1, 1995): 706–14. http://dx.doi.org/10.1139/g95-089.
Анотація:
A plasmid library of oat chromosome No21, the smallest chromosome of the complement, was constructed by microdissection and microcloning. The chromosome was deproteinized with proteinase K and digested with Sau3A and linker adaptors were ligated to the DNA fragments. From the single chromosome (less than 0.4 pg), 10 μg of DNA was obtained after 2 rounds of PCR amplification. Cloning experiments with the amplified DNA produced as many as 500 000 recombinant clones from the single chromosome. The 500 clones evaluated ranged in size from 150 to 1700 base pairs (bp) with an average size of 650 bp. These were approximately 41% high-copy and 59% low/unique copy clones. Tandem repeats were absent in the library and may have been selected against by a combination of the Sau3A digestion, which is sensitive to C-methylation, and the PCR amplification. Many low-copy dispersed repetitive sequences were present in the library. These were present primarily on A- and D-genome chromosomes. Southern blot analysis revealed that the unique-copy clones were suitable for restriction fragment length polymorphism analysis and that they mapped to the pertinent oat nullisomic lines.Key words: microdissection and microcloning, high density RFLP mapping, Sau3A linker adaptor, monosomics and nullisomics, Avena sativa L.
48
Smirlis, Despina, Haralabia Boleti, Maria Gaitanou, Manuel Soto, and Ketty Soteriadou. "Leishmania donovani Ran-GTPase interacts at the nuclear rim with linker histone H1." Biochemical Journal 424, no. 3 (December 10, 2009): 367–74. http://dx.doi.org/10.1042/bj20090576.
Анотація:
Ran-GTPase regulates multiple cellular processes such as nucleocytoplasmic transport, mitotic spindle assembly, nuclear envelope assembly, cell-cycle progression and the mitotic checkpoint. The leishmanial Ran protein, in contrast with its mammalian counterpart which is predominately nucleoplasmic, is localized at the nuclear rim. The aim of the present study was to characterize the LdRan (Leishmania donovani Ran) orthologue with an emphasis on the Ran–histone association. LdRan was found to be developmentally regulated, expressed 3-fold less in the amastigote stage. LdRan overexpression caused a growth defect linked to a delayed S-phase progression in promastigotes as for its mammalian counterpart. We report for the first time that Ran interacts with a linker histone, histone H1, in vitro and that the two proteins co-localize at the parasite nuclear rim. Interaction of Ran with core histones H3 and H4, creating in metazoans a chromosomal Ran-GTP gradient important for mitotic spindle assembly, is speculative in Leishmania spp., not only because this parasite undergoes a closed mitosis, but also because the main localization of LdRan is different from that of core histone H3. Interaction of Ran with the leishmanial linker histone H1 (LeishH1) suggests that this association maybe involved in modulation of pathways other than those documented for the metazoan Ran–core histone association.
49
Oda, Tsukasa, Toshiya Hayano, Hidenobu Miyaso, Nobuhiro Takahashi, and Takayuki Yamashita. "Hsp90 regulates the Fanconi anemia DNA damage response pathway." Blood 109, no. 11 (June 1, 2007): 5016–26. http://dx.doi.org/10.1182/blood-2006-08-038638.
Анотація:
Abstract Heat shock protein 90 (Hsp90) regulates diverse signaling pathways. Emerging evidence suggests that Hsp90 inhibitors, such as 17-allylamino-17-demethoxygeldanamycin (17-AAG), enhance DNA damage-induced cell death, suggesting that Hsp90 may regulate cellular responses to genotoxic stress. However, the underlying mechanisms are poorly understood. Here, we show that the Fanconi anemia (FA) pathway is involved in the Hsp90-mediated regulation of genotoxic stress response. In the FA pathway, assembly of 8 FA proteins including FANCA into a nuclear multiprotein complex, and the complex-dependent activation of FANCD2 are critical events for cellular tolerance against DNA cross-linkers. Hsp90 associates with FANCA, in vivo and in vitro, in a 17-AAG–sensitive manner. Disruption of the FANCA/Hsp90 association by cellular treatment with 17-AAG induces rapid proteasomal degradation and cytoplasmic relocalization of FANCA, leading to impaired activation of FANCD2. Furthermore, 17-AAG promotes DNA cross-linker–induced cytotoxicity, but this effect is much less pronounced in FA pathway-defective cells. Notably, 17-AAG enhances DNA cross-linker–induced chromosome aberrations. In conclusion, our results identify FANCA as a novel client of Hsp90, suggesting that Hsp90 promotes activation of the FA pathway through regulation of intracellular turnover and trafficking of FANCA, which is critical for cellular tolerance against genotoxic stress.
50
Gromova, M. A., Y. V. Kharitonov, Т. V. Rybalova, V. А. Larionov, T. S. Golubeva, and E. E. Shults. "Synthetic Transformations of Higher Terpenoids. 42. Synthesis of New 18-Nor-4-(Carboxyethyl)Isopimara-7,15-Diene Derivatives and Study of Their Cytotoxicity on MCF7, U-87 MG and DU 145 Cancer Cell Lines." Биоорганическая химия 49, no. 5 (September 1, 2023): 509–22. http://dx.doi.org/10.31857/s0132342323050032.
Анотація:
(E)-16-Aryl-substituted derivatives of tricyclic diterpenoids were synthesized by cross-coupling of isopimaric acid derivatives with substituted iodorenes catalyzed by palladium acetate in the presence of silver carbonate. Condensation of (E)-18-nor-4-(carboxyethyl)-16-(2-carboxyethyl)isopimar-7,15-diene dichloride with propargylamine hydrochloride leads to the corresponding dialkine, which readily reacts with diazide in the Cu(I) catalyzed cycloaddition (CuAAC) reaction, with the formation of macroheterocyclic compound containing a pimaran type tricyclic diterpenoid core and 1,2,3-triazole rings in the linker chain. Reaction of in situ prepared (E)-18-nor-16-azido-4-(carboxyethyl)isopimar-7,15-diene acid chloride with propargylamine hydrochloride or an alkynyl-substituted derivative of the protected Gly-Gly dipeptide leads to the corresponding azidoalkynes. The intramolecular CuAAC reaction of azidodipeptidylalkine afforded a macroheterocyclic derivative containing a dipeptide and triazole moiety in the linker chain. The obtained compounds showed higher (compared with the isopimaric acid) cytotoxicity on tumor cells MCF-7 and were less toxic to non-cancer cells than the reference drug doxorubicin. The GI50 value of the most active compound is 6.3 μM, selectivity index 15) (MTT test). The synthesized derivatives of the tricyclic diterpenoid isopimaric acid can be used to develop new antitumor agents.