Journal articles: 'Binding sites (Biochemistry) Ligand binding (Biochemistry)'

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Vidad, Ashley Ryan, Stephen Macaspac, and Ho Leung Ng. "Locating ligand binding sites in G-protein coupled receptors using combined information from docking and sequence conservation." PeerJ 9 (September 24, 2021): e12219. http://dx.doi.org/10.7717/peerj.12219.

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GPCRs (G-protein coupled receptors) are the largest family of drug targets and share a conserved structure. Binding sites are unknown for many important GPCR ligands due to the difficulties of GPCR recombinant expression, biochemistry, and crystallography. We describe our approach, ConDockSite, for predicting ligand binding sites in class A GPCRs using combined information from surface conservation and docking, starting from crystal structures or homology models. We demonstrate the effectiveness of ConDockSite on crystallized class A GPCRs such as the beta2 adrenergic and A2A adenosine receptors. We also demonstrate that ConDockSite successfully predicts ligand binding sites from high-quality homology models. Finally, we apply ConDockSite to predict the ligand binding sites on a structurally uncharacterized GPCR, GPER, the G-protein coupled estrogen receptor. Most of the sites predicted by ConDockSite match those found in other independent modeling studies. ConDockSite predicts that four ligands bind to a common location on GPER at a site deep in the receptor cleft. Incorporating sequence conservation information in ConDockSite overcomes errors introduced from physics-based scoring functions and homology modeling.

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Whittaker, Linda, Caili Hao, Wen Fu, and Jonathan Whittaker. "High-Affinity Insulin Binding: Insulin Interacts with Two Receptor Ligand Binding Sites†." Biochemistry 47, no. 48 (December 2, 2008): 12900–12909. http://dx.doi.org/10.1021/bi801693h.

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Linthicum, D. S., M. B. Bolger, P. H. Kussie, G. M. Albright, T. A. Linton, S. Combs, and D. Marchetti. "Analysis of idiotypic and anti-idiotypic antibodies as models of receptor and ligand." Clinical Chemistry 34, no. 9 (September 1, 1988): 1676–80. http://dx.doi.org/10.1093/clinchem/34.9.1676.

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Abstract Antibodies to small bioactive ligands and peptides may mimic the binding characteristics of the natural receptor; in turn, the anti-idiotypic antibodies generated against the binding sites of such anti-ligand antibodies may mimic some aspects of small bioactive ligands and peptides. Among the several levels of investigation of such antibody-receptor networks are (a) the quantitative structure-activity relationships of ligand binding to antibody as compared with natural receptor; (b) the molecular modeling of antibody-receptor binding sites and the genomic basis for such structures; and (c) the characteristics of the molecular mimicry exhibited by "mimetopes" on anti-idiotypic antibodies. To illustrate the analysis encountered at each of these levels, we discuss here antibody and anti-idiotypic systems that are directed to small neuroactive ligands and their receptors.

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Lummis, Sarah C. R. "Locating GABA in GABA receptor binding sites." Biochemical Society Transactions 37, no. 6 (November 19, 2009): 1343–46. http://dx.doi.org/10.1042/bst0371343.

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The Cys-loop family of ligand-gated ion channels contains both vertebrate and invertebrate members that are activated by GABA (γ-aminobutyric acid). Many of the residues that are critical for ligand binding have been identified in vertebrate GABAA and GABAC receptors, and specific interactions between GABA and some of these residues have been determined. In the present paper, I show how a cation–π interaction for one of the binding site residues has allowed the production of models of GABA docked into the binding site, and these orientations are supported by mutagenesis and functional data. Surprisingly, however, the residue that forms the cation–π interaction is not conserved, suggesting that GABA occupies subtly different locations even in such closely related receptors.

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Lin, Win, Michael P. Bernard, Donghui Cao, Rebecca V. Myers, John E. Kerrigan, and William R. Moyle. "Follitropin receptors contain cryptic ligand binding sites." Molecular and Cellular Endocrinology 260-262 (January 2007): 83–92. http://dx.doi.org/10.1016/j.mce.2006.06.012.

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Tozer, Eileen Collins, Paul E. Hughes, and Joseph C. Loftus. "Ligand binding and affinity modulation of integrins." Biochemistry and Cell Biology 74, no. 6 (December 1, 1996): 785–98. http://dx.doi.org/10.1139/o96-085.

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Integrins are cell adhesion receptors that mediate cell–cell and cell–extracellular matrix interactions. The extracellular domains of these receptors possess binding sites for a diverse range of protein ligands. Ligand binding is divalent cation dependent and involves well-defined motifs in the ligand. Integrins can dynamically regulate their affinity for ligands (inside-out signaling). This ability to rapidly modulate their affinity state is key to their involvement in such processes as cell migration and platelet aggregation. This review will focus on two aspects of integrin function: first, on the molecular basis of ligand–integrin interactions and, second, on the underlying mechanisms controlling the affinity state of integrins for their ligands.Key words: integrins, ligand binding, affinity modulation.

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Wang, Shiwei, Haoyu Lin, Zhixian Huang, Yufeng He, Xiaobing Deng, Youjun Xu, Jianfeng Pei, and Luhua Lai. "CavitySpace: A Database of Potential Ligand Binding Sites in the Human Proteome." Biomolecules 12, no. 7 (July 11, 2022): 967. http://dx.doi.org/10.3390/biom12070967.

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Location and properties of ligand binding sites provide important information to uncover protein functions and to direct structure-based drug design approaches. However, as binding site detection depends on the three-dimensional (3D) structural data of proteins, functional analysis based on protein ligand binding sites is formidable for proteins without structural information. Recent developments in protein structure prediction and the 3D structures built by AlphaFold provide an unprecedented opportunity for analyzing ligand binding sites in human proteins. Here, we constructed the CavitySpace database, the first pocket library for all the proteins in the human proteome, using a widely-applied ligand binding site detection program CAVITY. Our analysis showed that known ligand binding sites could be well recovered. We grouped the predicted binding sites according to their similarity which can be used in protein function prediction and drug repurposing studies. Novel binding sites in highly reliable predicted structure regions provide new opportunities for drug discovery. Our CavitySpace is freely available and provides a valuable tool for drug discovery and protein function studies.

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Gold, N. D., K. Deville, and R. M. Jackson. "New opportunities for protease ligand-binding site comparisons using SitesBase." Biochemical Society Transactions 35, no. 3 (May 22, 2007): 561–65. http://dx.doi.org/10.1042/bst0350561.

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The rapid expansion of structural information for protein ligand-binding sites is potentially an important source of information in structure-based drug design and in understanding ligand cross-reactivity and toxicity. We have developed SitesBase, a comprehensive database of ligand-binding sites extracted automatically from the Macromolecular Structure Database. SitesBase is an easily accessible database which is simple to use and holds pre-calculated information about structural similarities between known ligand-binding sites. These similarities are presented to the wider community enabling binding-site comparisons for therapeutically interesting protein families, such as the proteases and for new proteins to enable the discovery of interesting new structure–function relationships. The database is available from http://www.modelling.leeds.ac.uk/sb/.

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Puzon-McLaughlin, Wilma, Tetsuji Kamata, and Yoshikazu Takada. "Multiple Discontinuous Ligand-mimetic Antibody Binding Sites Define a Ligand Binding Pocket in Integrin αIIbβ3." Journal of Biological Chemistry 275, no. 11 (March 10, 2000): 7795–802. http://dx.doi.org/10.1074/jbc.275.11.7795.

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Anand, Praveen, Deepesh Nagarajan, Sumanta Mukherjee, and Nagasuma Chandra. "ABS–Scan: In silico alanine scanning mutagenesis for binding site residues in protein–ligand complex." F1000Research 3 (September 9, 2014): 214. http://dx.doi.org/10.12688/f1000research.5165.1.

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Most physiological processes in living systems are fundamentally regulated by protein–ligand interactions. Understanding the process of ligand recognition by proteins is a vital activity in molecular biology and biochemistry. It is well known that the residues present at the binding site of the protein form pockets that provide a conducive environment for recognition of specific ligands. In many cases, the boundaries of these sites are not well defined. Here, we provide a web-server to systematically evaluate important residues in the binding site of the protein that contribute towards the ligand recognition through in silico alanine-scanning mutagenesis experiments. Each of the residues present at the binding site is computationally mutated to alanine. The ligand interaction energy is computed for each mutant and the corresponding ΔΔG values are computed by comparing it to the wild type protein, thus evaluating individual residue contributions towards ligand interaction. The server will thus provide clues to researchers about residues to obtain loss-of-function mutations and to understand drug resistant mutations. This web-tool can be freely accessed through the following address: http://proline.biochem.iisc.ernet.in/abscan/.

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Anand, Praveen, Deepesh Nagarajan, Sumanta Mukherjee, and Nagasuma Chandra. "ABS–Scan: In silico alanine scanning mutagenesis for binding site residues in protein–ligand complex." F1000Research 3 (December 1, 2014): 214. http://dx.doi.org/10.12688/f1000research.5165.2.

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Most physiological processes in living systems are fundamentally regulated by protein–ligand interactions. Understanding the process of ligand recognition by proteins is a vital activity in molecular biology and biochemistry. It is well known that the residues present at the binding site of the protein form pockets that provide a conducive environment for recognition of specific ligands. In many cases, the boundaries of these sites are not well defined. Here, we provide a web-server to systematically evaluate important residues in the binding site of the protein that contribute towards the ligand recognition through in silico alanine-scanning mutagenesis experiments. Each of the residues present at the binding site is computationally mutated to alanine. The ligand interaction energy is computed for each mutant and the corresponding ΔΔG values are calculated by comparing it to the wild type protein, thus evaluating individual residue contributions towards ligand interaction. The server will thus provide a ranked list of residues to the user in order to obtain loss-of-function mutations. This web-tool can be freely accessed through the following address: http://proline.biochem.iisc.ernet.in/abscan/.

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Guo, Ting, Yanxin Shi, and Zhirong Sun. "A novel statistical ligand-binding site predictor: application to ATP-binding sites." Protein Engineering, Design and Selection 18, no. 2 (February 1, 2005): 65–70. http://dx.doi.org/10.1093/protein/gzi006.

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Chou, Wei-I., Tun-Wen Pai, Shi-Hwei Liu, Bor-Kai Hsiung, and Margaret D. T. Chang. "The family 21 carbohydrate-binding module of glucoamylase from Rhizopus oryzae consists of two sites playing distinct roles in ligand binding." Biochemical Journal 396, no. 3 (May 29, 2006): 469–77. http://dx.doi.org/10.1042/bj20051982.

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The starch-hydrolysing enzyme GA (glucoamylase) from Rhizopus oryzae is a commonly used glycoside hydrolase in industry. It consists of a C-terminal catalytic domain and an N-terminal starch-binding domain, which belong to the CBM21 (carbohydrate-binding module, family 21). In the present study, a molecular model of CBM21 from R. oryzae GA (RoGACBM21) was constructed according to PSSC (progressive secondary structure correlation), modified structure-based sequence alignment, and site-directed mutagenesis was used to identify and characterize potential ligand-binding sites. Our model suggests that RoGACBM21 contains two ligand-binding sites, with Tyr32 and Tyr67 grouped into site I, and Trp47, Tyr83 and Tyr93 grouped into site II. The involvement of these aromatic residues has been validated using chemical modification, UV difference spectroscopy studies, and both qualitative and quantitative binding assays on a series of RoGACBM21 mutants. Our results further reveal that binding sites I and II play distinct roles in ligand binding, the former not only is involved in binding insoluble starch, but also facilitates the binding of RoGACBM21 to long-chain soluble polysaccharides, whereas the latter serves as the major binding site mediating the binding of both soluble polysaccharide and insoluble ligands. In the present study we have for the first time demonstrated that the key ligand-binding residues of RoGACBM21 can be identified and characterized by a combination of novel bioinformatics methodologies in the absence of resolved three-dimensional structural information.

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Wilding, Matthew, Nansook Hong, Matthew Spence, Ashley M. Buckle, and Colin J. Jackson. "Protein engineering: the potential of remote mutations." Biochemical Society Transactions 47, no. 2 (March 22, 2019): 701–11. http://dx.doi.org/10.1042/bst20180614.

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Abstract Engineered proteins, especially enzymes, are now commonly used in many industries owing to their catalytic power, specific binding of ligands, and properties as materials and food additives. As the number of potential uses for engineered proteins has increased, the interest in engineering or designing proteins to have greater stability, activity and specificity has increased in turn. With any rational engineering or design pursuit, the success of these endeavours relies on our fundamental understanding of the systems themselves; in the case of proteins, their structure–dynamics–function relationships. Proteins are most commonly rationally engineered by targeting the residues that we understand to be functionally important, such as enzyme active sites or ligand-binding sites. This means that the majority of the protein, i.e. regions remote from the active- or ligand-binding site, is often ignored. However, there is a growing body of literature that reports on, and rationalises, the successful engineering of proteins at remote sites. This minireview will discuss the current state of the art in protein engineering, with a particular focus on engineering regions that are remote from active- or ligand-binding sites. As the use of protein technologies expands, exploiting the potential improvements made possible through modifying remote regions will become vital if we are to realise the full potential of protein engineering and design.

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Koehbach, Johannes, Thomas Stockner, Christian Bergmayr, Markus Muttenthaler, and Christian W. Gruber. "Insights into the molecular evolution of oxytocin receptor ligand binding." Biochemical Society Transactions 41, no. 1 (January 29, 2013): 197–204. http://dx.doi.org/10.1042/bst20120256.

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The design and development of selective ligands for the human OT (oxytocin) and AVP (arginine vasopressin) receptors is a big challenge since the different receptor subtypes and their native peptide ligands display great similarity. Detailed understanding of the mechanism of OT's interaction with its receptor is important and may assist in the ligand- or structure-based design of selective and potent ligands. In the present article, we compared 69 OT- and OT-like receptor sequences with regards to their molecular evolution and diversity, utilized an in silico approach to map the common ligand interaction sites of recently published G-protein-coupled receptor structures to a model of the human OTR (OT receptor) and compared these interacting residues within a selection of different OTR sequences. Our analysis suggests the existence of a binding site for OT peptides within the common transmembrane core region of the receptor, but it appears extremely difficult to identify receptor or ligand residues that could explain the selectivity of OT to its receptors. We remain confident that the presented evolutionary overview and modelling approach will aid interpretation of forthcoming OTR crystal structures.

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Mondoro, TH, CD Wall, MM White, and LK Jennings. "Selective induction of a glycoprotein IIIa ligand-induced binding site by fibrinogen and von Willebrand factor." Blood 88, no. 10 (November 15, 1996): 3824–30. http://dx.doi.org/10.1182/blood.v88.10.3824.bloodjournal88103824.

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Ligand-induced binding sites (LIBS) are neoantigenic regions of glycoprotein (GP)IIb-IIIa that are exposed upon interaction of the receptor with the ligand fibrinogen or the ligand recognition sequence (RGDS). LIBS have been suggested to contribute to postreceptor occupancy events such as full-scale platelet aggregation, adhesion to collagen, and clot retraction. This study examined the induction requirements of a GPIIIa LIBS with regard to ligand specificity. Through the use of the anti-LIBS D3, we report that this complex- activating antibody induces fibrinogen-and von Willebrand factor-binding to GPIIb-IIIa on intact platelets. Bound ligand was detected by flow cytometric analysis and platelet aggregation assays. These bound ligands increased the number of D3-binding sites and altered the affinity of D3 for GPIIb-IIIa on platelets. In contrast, activation of platelet GPIIb-IIIa by D3 did not increase the binding of another RGD- containing ligand, vitronectin. Furthermore, bound vitronectin on thrombin-stimulated platelets did not cause the expression of the D3 LIBS epitope. We conclude direct activation of GPIIb-IIIa in the absence of platelet activation results in selective ligand interaction and that D3 LIBS induction requires the binding of the multivalent ligands, fibrinogen or von Willebrand factor. Thus, the region of GPIIIa recognized by D3 may be an important regulatory domain in ligand- receptor interactions that directly mediate platelet aggregation.

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Kozielski, Frank, Céleste Sele, Vladimir O. Talibov, Jiaqi Lou, Danni Dong, Qian Wang, Xinyue Shi, et al. "Identification of fragments binding to SARS-CoV-2 nsp10 reveals ligand-binding sites in conserved interfaces between nsp10 and nsp14/nsp16." RSC Chemical Biology 3, no. 1 (2022): 44–55. http://dx.doi.org/10.1039/d1cb00135c.

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By fragment screening using X-ray crystallography we identified four ligands revealing ligand-binding sites in interfaces between SARS-CoV-2 nsp10 and nsp14/nsp16. The nsp14/10 interaction is weak and therefore could be disrupted by small molecules.

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Komiyama, Yusuke, Masaki Banno, Kokoro Ueki, Gul Saad, and Kentaro Shimizu. "Automatic generation of bioinformatics tools for predicting protein–ligand binding sites." Bioinformatics 32, no. 6 (November 5, 2015): 901–7. http://dx.doi.org/10.1093/bioinformatics/btv593.

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Abstract Motivation: Predictive tools that model protein–ligand binding on demand are needed to promote ligand research in an innovative drug-design environment. However, it takes considerable time and effort to develop predictive tools that can be applied to individual ligands. An automated production pipeline that can rapidly and efficiently develop user-friendly protein–ligand binding predictive tools would be useful. Results: We developed a system for automatically generating protein–ligand binding predictions. Implementation of this system in a pipeline of Semantic Web technique-based web tools will allow users to specify a ligand and receive the tool within 0.5–1 day. We demonstrated high prediction accuracy for three machine learning algorithms and eight ligands. Availability and implementation: The source code and web application are freely available for download at http://utprot.net. They are implemented in Python and supported on Linux. Contact: shimizu@bi.a.u-tokyo.ac.jp Supplementary information: Supplementary data are available at Bioinformatics online.

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Craenenbroeck, Elke Van, Jo Vercammen, Gunther Matthys, Jan Beirlant, Christophe Marot, Johan Hoebeke, Rik Strobbe, and Yves Engelborghs. "Heuristic Statistical Analysis of Fluorescence Fluctuation Data with Bright Spikes: Application to Ligand Binding to the Human Serotonin Receptor Expressed in Escherichia coli Cells." Biological Chemistry 382, no. 3 (March 21, 2001): 355–61. http://dx.doi.org/10.1515/bc.2001.043.

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Abstract A statistical method for the analysis of fluorescence fluctuation amplitudes including bright spikes is presented. This situation arises e. g. when fluorescent ligands interact with receptors carrying multiple binding sites. The technique gives information on the amount of bound ligand in solution, making it a complementary technique to fluorescence correlation spectroscopy analysis, which cannot be applied in this situation. Two simple statistical tests are proposed that can discriminate between fluorescence intensities originating from free ligands or complexes. The performance of the two tests is evaluated and compared on mixtures of a fluorophore and fluorophore coated beads that mimic the behaviour of multiliganded complexes. An application to ligand binding to the serotonin receptor, expressed on Escherichia coli cells, is also provided. Specific binding of a fluorophore to this receptor, as well as competition with several ligands, is assessed.

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Pandey, Vishnudatt, Gargi Tiwari, and Rajendra Prasad Ojha. "A Comparative Study of Binding of Different Drugs on gp120: Insight from Molecular Dynamics Simulation Study." Oriental Journal of Chemistry 34, no. 6 (November 23, 2018): 2954–62. http://dx.doi.org/10.13005/ojc/340635.

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HIV-I cellular infection triggered by CD4 receptor protein and viral envelop glycoprotein gp120 binding event. CD4:gp120 surface is directed by the contact points of a hydrophobic gp120 cavity capped by Phe43CD4 and ionic bonds residues Arg59CD4 and Asp368gp120. The binding sites originated by gp120 and CD4 interaction leads to the entry of HIV-I into the host membrane, where, gp120 and a CD4 binding site becomes the main mark for plenty of drug uncovering program. Here, we took the crystal structure of small-molecule of gp120 in a complex that concurrently pursues both of the hotspots of gp120 binding sites. All ligands in our study are small molecules that are able to obstruct the protein-protein interactions between CD4 and gp120. This study aims at the thermodynamical insights of the ligand binding in CD4 binding sites using Molecular Dynamics Simulations Study and calculation of binding free energy. The physical of binding of drugs distinctly indicates a hydrophobic and electrostatics interaction motivated binding of ligands which explicitly mark CD4 binding sites.

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Micucci, Joseph A., Parvathi Kamath, Anuja Khan, Paul E. Bock, and Sriram Krishnaswamy. "Long-Range Allosteric Linkage Between Exosites Reciprocally Regulates the Zymogenicity of Prothrombin Derivatives." Blood 126, no. 23 (December 3, 2015): 122. http://dx.doi.org/10.1182/blood.v126.23.122.122.

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Abstract The binding of ligands to anion binding exosite I (ABEI) and exosite II (ABEII) on prothrombin (II) derivatives plays an integral role in regulating their function. These exosites are located on opposite faces of the proteinase domain and exhibit unique binding specificities. Fragment 1.2 (F12) binds to ABEII and acts as a zymogen-promoting allosteric ligand. Conversely, Na+ and active site ligands stabilize the proteinase state. Here, we investigated the allosteric linkage between ABEI and the Na+ binding site, active site or ABEII using multiple ABEI ligands and prothrombin derivatives differentially poised along the zymogen to proteinase continuum. Prethrombin 2 (P2) represents the most zymogen-like state that differs from thrombin (IIa) because it is not cleaved at the R320 site. To mimic the zymogen-like character of P2 in a cleaved IIa molecule, residues responsible for N-terminal insertion and proteinase formation (IVE) were swapped with TAT to produce IIaTAT, a mutant with vastly diminished proteolytic activity. Alanine was substituted with the catalytic serine residue in IIa (IIaS195A) to represent the proteinase without a ligand at its active site. The thermodynamics of interactions between the thrombin inhibitor and ABEI ligand hirugen (Hir) and the various reference states was assessed using isothermal titration calorimetry (ITC). Titration of Hir into P2, IIaTAT or IIaS195A revealed thermodynamically more favorable binding to proteinase-like IIaS195A in comparison to zymogen-like P2 or IIaTAT. Binding of Hir to IIaS195A was affected by the concentration of Na+ at constant ionic strength. Global analysis done in the presence of increasing concentrations of Na+ revealed a 5-fold increase in Hir binding affinity when IIaS195A is ligated with Na+; demonstrating positive allosteric linkage between ABEI and Na+ binding. Using a truncated Staphylocoagulase variant that binds ABEI without N-terminus insertion (SC13-325), we found that SC13-325 binding alone promoted active site opening and fluorescent inhibitor incorporation in zymogen-like P2. These data reinforce the observation that ABEI ligands promote a proteinase-like state in prothrombin derivatives through positive allosteric linkage with the Na+ binding and active sites. Interestingly, inhibitor incorporation and ITC studies both showed that SC13-325 interacts poorly with II, but strongly with P2 despite both species being zymogens. These findings imply that the ABEII ligand F12, which is produced upon cleavage of II at R271 to form P2, may display negative allosteric linkage with ABEI. Titration of SC13-325 into pre-formed complexes of P2/F12 revealed a drastic reduction in affinity of SC13-325 for P2 when F12 is bound to ABEII. Thus, F12 binding at ABEII negatively affects ABEI binding. Further studies used soluble thrombomodulin (sTM) as the most physiologically pertinent ligand for ABEI. ITC and global analysis of the binding of F12 to P2 in the presence of different concentrations of sTM revealed a ~1200-fold decrease in binding affinity and enthalpy for either the binding of F12 to P2 bound to sTM or the binding of sTM to P2 bound to F12. These data illustrate the strong negative linkage associated with the binding of protein ligands to ABEI and ABEII which yields the appearance of competitive and mutually exclusive binding at the two sites despite the fact that they are on opposite sides of the proteinase domain. Allosteric linkage between ligand binding at the two exosites is centered on the ability of F12 binding to ABEII and favor zymogen-like forms and ligand binding to ABEI to favor proteinase-like forms. Thus, allosteric linkage among exosites is vital to the interconversion of prothrombin species along the zymogen to proteinase spectrum. These ligand-dependent conformational shifts and associated changes in function are likely to greatly contribute to the dynamic roles that IIa plays during coagulation. Disclosures No relevant conflicts of interest to declare.

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Heegaard, Niels H. H., Peter M. H. Heegaard, Peter Roepstorff, and Frank A. Robey. "Ligand-Binding Sites in Human Serum Amyloid P Component." European Journal of Biochemistry 239, no. 3 (August 1996): 850–56. http://dx.doi.org/10.1111/j.1432-1033.1996.0850u.x.

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Mohamad, Nada, Ailsa O'Donoghue, Anastassia L. Kantsadi, and Ioannis Vakonakis. "Structures of the Plasmodium falciparum heat-shock protein 70-x ATPase domain in complex with chemical fragments identify conserved and unique binding sites." Acta Crystallographica Section F Structural Biology Communications 77, no. 8 (July 28, 2021): 262–68. http://dx.doi.org/10.1107/s2053230x21007378.

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Plasmodium falciparum invades erythrocytes and extensively modifies them in a manner that increases the virulence of this malaria parasite. A single heat-shock 70 kDa-type chaperone, PfHsp70-x, is among the parasite proteins exported to the host cell. PfHsp70-x assists in the formation of a key protein complex that underpins parasite virulence and supports parasite growth during febrile episodes. Previous work resolved the crystallographic structures of the PfHsp70-x ATPase and substrate-binding domains, and showed them to be highly similar to those of their human counterparts. Here, 233 chemical fragments were screened for binding to the PfHsp70-x ATPase domain, resulting in three crystallographic structures of this domain in complex with ligands. Two binding sites were identified, with most ligands binding proximal to the ATPase nucleotide-binding pocket. Although amino acids participating in direct ligand interactions are conserved between the parasite and human erythrocytic chaperones, one nonconserved residue is also present near the ligand. This work suggests that PfHsp70-x features binding sites that may be exploitable by small-molecule ligands towards the specific inhibition of the parasite chaperone.

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Anolik, Jennifer H., Carolyn M. Klinge, Russell Hilf, and Robert A. Bambara. "Cooperative binding of estrogen receptor to DNA depends on spacing of binding sites, flanking sequence, and ligand." Biochemistry 34, no. 8 (February 1995): 2511–20. http://dx.doi.org/10.1021/bi00008a015.

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Soshilov, Anatoly, and Michael S. Denison. "Ligand Displaces Heat Shock Protein 90 from Overlapping Binding Sites within the Aryl Hydrocarbon Receptor Ligand-binding Domain." Journal of Biological Chemistry 286, no. 40 (August 19, 2011): 35275–82. http://dx.doi.org/10.1074/jbc.m111.246439.

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Neumann, P., V. Cody, and A. Wojtczak. "Structural basis of negative cooperativity in transthyretin." Acta Biochimica Polonica 48, no. 4 (December 31, 2001): 867–75. http://dx.doi.org/10.18388/abp.2001_3852.

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A comparison of the AC and BD binding sites of transthyretin (TTR) was made in terms of the interatomic distances between the Ca atoms of equivalent amino acids, measured across the tetramer channel in each binding site. The comparison of the channel diameter for apo TTR from different sources revealed that in the unliganded transthyretin tetramers the distances between the A, D and H beta-strands are consistently larger, while the distances between the G beta-strands are smaller in one site than in the other. These differences might be described to have a 'wave' character. An analogous analysis performed for transthyretin complexes reveals that the shape of the plot is similar, although the amplitudes of the changes are smaller. The analysis leads us to a model of the changes in the binding sites caused by ligand binding. The sequence of events includes ligand binding in the first site, followed by a slight collapse of this site and concomitant opening of the second site, binding of the second molecule and collapse of the second site. The following opening of the first, already occupied site upon ligand binding in the second site is smaller because of the bridging interactions already formed by the first ligand. This explains the negative cooperativity (NC) effect observed for many ligands in transthyretin.

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Honda, Shigenori, Yoshiaki Tomiyama, Nisar Pampori, Hirokazu Kashiwagi, Teruo Kiyoi, Satoru Kosugi, Seiji Tadokoro, Yoshiyuki Kurata, Sanford J. Shattil, and Yuji Matsuzawa. "Ligand binding to integrin αvβ3requires tyrosine 178 in the αv subunit." Blood 97, no. 1 (January 1, 2001): 175–82. http://dx.doi.org/10.1182/blood.v97.1.175.

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Abstract Integrin αvβ3 has been implicated in angiogenesis and other biological processes. However, the ligand-binding sites in αv, a non–I-domain α subunit, remain to be identified. Recently in αIIb, the other partner of the β3 subunit, several discontinuous residues important for ligand binding were identified in the predicted loops between repeats 2 and 3 (W3 4-1 loop) and within repeat 3 (W3 2-3 loop). Based on these findings, alanine-scanning mutagenesis in 293 cells was used to investigate the role of these loops (cysteine [C]142-C155 and glycine [G]172-G181) of αv in ligand binding. Wild-type αvβ3 was able to bind soluble fibrinogen following integrin activation either by 0.5 mM manganese dichloride (MnCl2) or a mutation of β3 threonine (T)562 to asparagine. However, mutation of tyrosine (Y)178 to alanine in the predicted G172-G181 loop of αv abolished fibrinogen binding, and alanine (A) substitutions at adjacent residues phenylalanine (F)177 and tryptophan (W)179 had a similar effect. Cells expressing Y178Aαvalso failed to bind to immobilized fibrinogen. Moreover, the Y178A mutation abolished the binding of WOW-1 Fab, a monovalent ligand-mimetic anti-αvβ3 antibody, and the expression of β3 ligand–induced binding sites (LIBS) induced by arginine-glycine-aspartic acid-tryptophan (RGDW). In sharp contrast to the data obtained with αIIb, none of the mutations in the predicted W3 4-1 loop in αv impaired ligand binding. These results implicate αv Y178 in ligand binding to αvβ3, and they suggest that there are key structural differences in the adhesive ligand-binding sites of αvβ3 and αIIbβ3.

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Glennon, Richard A., George Battaglia, and J. Doyle Smith. "(-)PPAP: A new and selective ligand for sigma binding sites." Pharmacology Biochemistry and Behavior 37, no. 3 (November 1990): 557–59. http://dx.doi.org/10.1016/0091-3057(90)90027-f.

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IVÁN, GÁBOR, ZOLTÁN SZABADKA, and VINCE GROLMUSZ. "ON THE ASYMMETRY OF THE RESIDUE COMPOSITIONS OF THE BINDING SITES ON PROTEIN SURFACES." Journal of Bioinformatics and Computational Biology 07, no. 06 (December 2009): 931–38. http://dx.doi.org/10.1142/s0219720009004394.

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By screening all the ligand binding sites in the Protein Data Bank, we have found that while it is geometrically possible that a loop, formed from a protein chain with residues ZYX, would "impersonate" another chain-loop with residues XYZ by a simple twisting of either the loop or the bound ligand, it almost never happens. This fact is rather surprising, and implies a notable asymmetry, since (i) loops in the folded proteins sometimes can be flexible enough to be twisted, but (ii) ligands are almost always extremely mobile before binding to the protein, therefore they can turn around and bind to residue-sequence ZYX as well. Data availability: The supplementary Table 3 lists the appearances of the residue-sequences and their inverses in the binding sites of the whole PDB, and is available at .

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Miller, Catherine M., Sandra S. Szegedi, and Timothy A. Garrow. "Conformation-dependent inactivation of human betaine-homocysteine S-methyltransferase by hydrogen peroxide in vitro." Biochemical Journal 392, no. 3 (December 6, 2005): 443–48. http://dx.doi.org/10.1042/bj20050356.

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Betaine-homocysteine S-methyltransferase (BHMT) transfers a methyl group from betaine to Hcy to form DMG (dimethylglycine) and Met. The reaction is ordered Bi Bi; Hcy is the first substrate to bind and Met is the last product off. Using intrinsic tryptophan fluorescence [Castro, Gratson, Evans, Jiracek, Collinsova, Ludwig and Garrow (2004) Biochemistry 43, 5341–5351], it was shown that BHMT exists in three steady-state conformations: enzyme alone, enzyme plus occupancy at the first substrate-binding site (Hcy or Met), or enzyme plus occupancy at both substrate-binding sites (Hcy plus betaine, or Hcy plus DMG). Betaine or DMG alone do not bind to the enzyme, indicating that the conformational change associated with Hcy binding creates the betaine-binding site. CBHcy [S-(δ-carboxybutyl)-D,L-homocysteine] is a bisubstrate analogue that causes BHMT to adopt the same conformation as the ternary complexes. We report that BHMT is susceptible to conformation-dependent oxidative inactivation. Two oxidants, MMTS (methyl methanethiosulphonate) and hydrogen peroxide (H2O2), cause a loss of the enzyme's catalytic Zn (Zn2+ ion) and a correlative loss of activity. Addition of 2-mercaptoethanol and exogenous Zn after MMTS treatment restores activity, but oxidation due to H2O2 is irreversible. CD and glutaraldehyde cross-linking indicate that H2O2 treatment causes small perturbations in secondary structure but no change in quaternary structure. Oxidation is attenuated when both binding sites are occupied by CBHcy, but Met alone has no effect. Partial digestion of ligand-free BHMT with trypsin produces two large peptides, excising a seven-residue peptide within loop L2. CBHcy but not Met binding slows down proteolysis by trypsin. These findings suggest that L2 is involved in the conformational change associated with occupancy at the betaine-binding site and that this conformational change and/or occupancy at both ligand-binding sites protect the enzyme from oxidative inactivation.

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Loch, Joanna I., Jakub Barciszewski, Joanna Śliwiak, Piotr Bonarek, Paulina Wróbel, Kinga Pokrywka, Ivan G. Shabalin, Wladek Minor, Mariusz Jaskolski, and Krzysztof Lewiński. "New ligand-binding sites identified in the crystal structures of β-lactoglobulin complexes with desipramine." IUCrJ 9, no. 3 (April 29, 2022): 386–98. http://dx.doi.org/10.1107/s2052252522004183.

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The homodimeric β-lactoglobulin belongs to the lipocalin family of proteins that transport a wide range of hydrophobic molecules and can be modified by mutagenesis to develop specificity for novel groups of ligands. In this work, new lactoglobulin variants, FAF (I56F/L39A/M107F) and FAW (I56F/L39A/M107W), were produced and their interactions with the tricyclic drug desipramine (DSM) were studied using X-ray crystallography, calorimetry (ITC) and circular dichroism (CD). The ITC and CD data showed micromolar affinity of the mutants for DSM and interactions according to the classical one-site binding model. However, the crystal structures unambiguously showed that the FAF and FAW dimers are capable of binding DSM not only inside the β-barrel as expected, but also at the dimer interface and at the entrance to the binding pocket. The presented high-resolution crystal structures therefore provide important evidence of the existence of alternative ligand-binding sites in the β-lactoglobulin molecule. Analysis of the crystal structures highlighted the importance of shape complementarity for ligand recognition and selectivity. The binding sites identified in the crystal structures of the FAF–DSM and FAW–DSM complexes together with data from the existing literature are used to establish a systematic classification of the ligand-binding sites in the β-lactoglobulin molecule.

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Khasawneh, Fadi T., Jin-Sheng Huang, Joseph W. Turek, and Guy C. Le Breton. "Differential Mapping of the Amino Acids Mediating Agonist and Antagonist Coordination with the Human Thromboxane A2 Receptor Protein." Blood 106, no. 11 (November 16, 2005): 3571. http://dx.doi.org/10.1182/blood.v106.11.3571.3571.

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Abstract Despite the well-documented involvement of thromboxane A2 receptor (TPR) signaling in the pathogenesis of thrombotic diseases, there are currently no rationally-designed antagonists available for clinical use. To a large extent this derives from a lack of knowledge regarding the topography of the TPR ligand binding pocket. On this basis, the purpose of the current study was to identify the specific amino acid residues in the TPR protein which regulate ligand coordination and binding. The sites selected for mutation reside within or in close proximity to a region we previously defined as a TPR ligand binding site, i.e., the C-terminus of the second extracellular loop and the leading edge of the fifth transmembrane domain. Mutation of these residues caused varying effects on the TPR-ligand coordination process. Specifically, the D193A mutant lacked both SQ29,548 (antagonist) binding and U46619 (agonist)-induced calcium mobilization. Three other mutants, F184Y, T186A and S191T, discriminated between SQ29,548 binding and the U46619-mediated functional response. Furthermore, these mutants also revealed a divergence in the binding of two structurally different antagonists, SQ29,548 and BM13.505. Conversely, two separate mutants which exhibited SQ29,548 binding activity yielded either a normal (F196Y) or reduced (S201T) U46619 response. Finally, mutation of other residues directly adjacent to those described above, e.g., E190A and F200A, produced no detectable effects on either SQ29,548 binding or the U46619-induced functional response. In summary, these results identify key amino acids involved in TPR ligand coordination and demonstrate that TPR-specific ligands do not necessarily interact with the same residues in the ligand-binding pocket.

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Henshaw, Joanna L., David N. Bolam, Virgínia M. R. Pires, Mirjam Czjzek, Bernard Henrissat, Luis M. A. Ferreira, Carlos M. G. A. Fontes, and Harry J. Gilbert. "The Family 6 Carbohydrate Binding ModuleCmCBM6-2 Contains Two Ligand-binding Sites with Distinct Specificities." Journal of Biological Chemistry 279, no. 20 (March 5, 2004): 21552–59. http://dx.doi.org/10.1074/jbc.m401620200.

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Esko, Jeffrey D., and Scott B. Selleck. "Order Out of Chaos: Assembly of Ligand Binding Sites in Heparan Sulfate." Annual Review of Biochemistry 71, no. 1 (June 2002): 435–71. http://dx.doi.org/10.1146/annurev.biochem.71.110601.135458.

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Singh, Sanjay K., Avinash Thirumalai, Asmita Pathak, Donald N. Ngwa, and Alok Agrawal. "Functional Transformation of C-reactive Protein by Hydrogen Peroxide." Journal of Biological Chemistry 292, no. 8 (January 17, 2017): 3129–36. http://dx.doi.org/10.1074/jbc.m116.773176.

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C-reactive protein (CRP) is present at sites of inflammation including amyloid plaques, atherosclerotic lesions, and arthritic joints. CRP, in its native pentameric structural conformation, binds to cells and molecules that have exposed phosphocholine (PCh) groups. CRP, in its non-native pentameric structural conformation, binds to a variety of deposited, denatured, and aggregated proteins, in addition to binding to PCh-containing substances. In this study, we investigated the effects of H2O2, a prototypical reactive oxygen species that is also present at sites of inflammation, on the ligand recognition function of CRP. Controlled H2O2 treatment of native CRP did not monomerize CRP and did not affect the PCh binding activity of CRP. In solid phase ELISA-based ligand binding assays, purified pentameric H2O2-treated CRP bound to a number of immobilized proteins including oxidized LDL, IgG, amyloid β peptide 1–42, C4b-binding protein, and factor H, in a CRP concentration- and ligand concentration-dependent manner. Using oxidized LDL as a representative protein ligand for H2O2-treated CRP, we found that the binding occurred in a Ca2+-independent manner and did not involve the PCh-binding site of CRP. We conclude that H2O2 is a biological modifier of the structure and ligand recognition function of CRP. Overall, the data suggest that the ligand recognition function of CRP is dependent on the presence of an inflammatory microenvironment. We hypothesize that one of the functions of CRP at sites of inflammation is to sense the inflammatory microenvironment, change its own structure in response but remain pentameric, and then bind to pathogenic proteins deposited at those sites.

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Shi, Wentao, Manali Singha, Limeng Pu, Gopal Srivastava, Jagannathan Ramanujam, and Michal Brylinski. "GraphSite: Ligand Binding Site Classification with Deep Graph Learning." Biomolecules 12, no. 8 (July 29, 2022): 1053. http://dx.doi.org/10.3390/biom12081053.

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The binding of small organic molecules to protein targets is fundamental to a wide array of cellular functions. It is also routinely exploited to develop new therapeutic strategies against a variety of diseases. On that account, the ability to effectively detect and classify ligand binding sites in proteins is of paramount importance to modern structure-based drug discovery. These complex and non-trivial tasks require sophisticated algorithms from the field of artificial intelligence to achieve a high prediction accuracy. In this communication, we describe GraphSite, a deep learning-based method utilizing a graph representation of local protein structures and a state-of-the-art graph neural network to classify ligand binding sites. Using neural weighted message passing layers to effectively capture the structural, physicochemical, and evolutionary characteristics of binding pockets mitigates model overfitting and improves the classification accuracy. Indeed, comprehensive cross-validation benchmarks against a large dataset of binding pockets belonging to 14 diverse functional classes demonstrate that GraphSite yields the class-weighted F1-score of 81.7%, outperforming other approaches such as molecular docking and binding site matching. Further, it also generalizes well to unseen data with the F1-score of 70.7%, which is the expected performance in real-world applications. We also discuss new directions to improve and extend GraphSite in the future.

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Askari, A., S. S. Kakar, and W. H. Huang. "Ligand binding sites of the ouabain-complexed (Na+ + K+)-ATPase." Journal of Biological Chemistry 263, no. 1 (January 1988): 235–42. http://dx.doi.org/10.1016/s0021-9258(19)57383-5.

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Haider, Shozeb M., and Stephen Neidle. "A molecular model for drug binding to tandem repeats of telomeric G-quadruplexes." Biochemical Society Transactions 37, no. 3 (May 20, 2009): 583–88. http://dx.doi.org/10.1042/bst0370583.

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The extreme 3′-ends of human telomeres consist of 150–250 nucleotides of single-stranded DNA sequence together with associated proteins. Small-molecule ligands can compete with these proteins and induce a conformational change in the DNA to a four-stranded quadruplex arrangement, which is also no longer a substrate for the telomerase enzyme. The modified telomere ends provide signals to the DNA-damage-response system and trigger senescence and apoptosis. Experimental structural data are available on such quadruplex complexes comprising up to four telomeric DNA repeats, but not on longer systems that are more directly relevant to the single-stranded overhang in human cells. The present paper reports on a molecular modelling study that uses Molecular Dynamics simulation methods to build dimer and tetramer quadruplex repeats. These incorporate ligand-binding sites and are models for overhang–ligand complexes.

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Bond, Jeffrey P., and Angelo C. Notides. "A chemical kinetic model for ligand binding to identical and independent binding sites in vivo." Analytical Biochemistry 175, no. 1 (November 1988): 238–51. http://dx.doi.org/10.1016/0003-2697(88)90384-3.

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40

Liu, Guangzhong, Min Liu, Daozheng Chen, Lei Chen, Jiali Zhu, Bo Zhou, and Jun Gao. "Predicting Protein Ligand Binding Sites with Structure Alignment Method on Hadoop." Current Proteomics 13, no. 2 (June 13, 2016): 113–21. http://dx.doi.org/10.2174/157016461302160514003915.

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41

Yang, Hua, Yan-Lin Liu, Yuan-Yuan Tao, Wei Yang, Chun-Ping Yang, Jing Zhang, Li-Zhi Qian, Hao Liu, and Zhi-Yong Wang. "Bioinformatic and biochemical analysis of the key binding sites of the pheromone binding protein of Cyrtotrachelus buqueti Guerin-Meneville (Coleoptera: Curculionidea)." PeerJ 7 (October 14, 2019): e7818. http://dx.doi.org/10.7717/peerj.7818.

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The bamboo snout beetle Cyrtotrachelus buqueti is a widely distributed wood-boring pest found in China, and its larvae cause significant economic losses because this beetle targets a wide range of host plants. A potential pest management measure of this beetle involves regulating olfactory chemoreceptors. In the process of olfactory recognition, pheromone-binding proteins (PBPs) play an important role. Homology modeling and molecular docking were conducted in this study for the interaction between CbuqPBP1 and dibutyl phthalate to better understand the relationship between PBP structures and their ligands. Site-directed mutagenesis and binding experiments were combined to identify the binding sites of CbuqPBP1 and to explore its ligand-binding mechanism. The 3D structural model of CbuqPBP1 has six a-helices. Five of these a-helices adopt an antiparallel arrangement to form an internal ligand-binding pocket. When docking dibutyl phthalate within the active site of CbuqPBP1, a CH-π interaction between the benzene ring of dibutyl phthalate and Phe69 was observed, and a weak hydrogen bond formed between the ester carbonyl oxygen and His53. Thus, Phe69 and His53 are predicted to be important residues of CbuqPBP1 involved in ligand recognition. Site-directed mutagenesis and fluorescence assays with a His53Ala CbuqPBP1 mutant showed no affinity toward ligands. Mutation of Phe69 only affected binding of CbuqPBP1 to cedar camphor. Thus, His53 (Between α2 and α3) of CbuqPBP1 appears to be a key binding site residue, and Phe69 (Located at α3) is a very important binding site for particular ligand interactions.

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Lecut, Christelle, Véronique Arocas, Hans Ulrichts, Anthony Elbaz, Jean-Luc Villeval, Jean-Jacques Lacapère, Hans Deckmyn, and Martine Jandrot-Perrus. "Identification of Residues within Human Glycoprotein VI Involved in the Binding to Collagen." Journal of Biological Chemistry 279, no. 50 (October 4, 2004): 52293–99. http://dx.doi.org/10.1074/jbc.m406342200.

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Glycoprotein VI (GPVI) has a crucial role in platelet responses to collagen. Still, little is known about its interaction with its ligands. In binding assays using soluble or cell-expressed human GPVI, we observed that (i) collagen, and the GPVI-specific ligands collagen-related peptides (CRP) and convulxin, competed with one another for the binding to GPVI and (ii) monoclonal antibodies directed against the extracellular part of the human receptor displayed selective inhibitory properties on GPVI interaction with its ligands. Monoclonal antibody 9E18 strongly reduced the binding of GPVI to collagen/CRP, 3F8 inhibited its interaction with convulxin, whereas 9O12 prevented all three interactions. These observations suggest that ligand-binding sites are distinct, exhibiting specific features but at the same time also sharing some common residues participating in the recognition of these ligands. The epitope of 9O12 was mapped by phage display, along with molecular modeling of human GPVI, which allowed the identification of residues within GPVI potentially involved in ligand recognition. Site-directed mutagenesis revealed that valine 34 and leucine 36 are critical for GPVI interaction with collagen and CRP. The loop might thus be part of a collagen/CRP-binding site.

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43

Starmer, C. F., D. L. Packer, and A. O. Grant. "Ligand binding to transiently accessible sites: Mechanisms for varying apparent binding rates." Journal of Theoretical Biology 124, no. 3 (February 1987): 335–41. http://dx.doi.org/10.1016/s0022-5193(87)80120-0.

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44

Nagao, M., S. Matsumoto, S. Masuda, and R. Sasaki. "Effect of tunicamycin treatment on ligand binding to the erythropoietin receptor: conversion from two classes of binding sites to a single class." Blood 81, no. 10 (May 15, 1993): 2503–10. http://dx.doi.org/10.1182/blood.v81.10.2503.2503.

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Abstract Scatchard analyses of erythropoietin (EPO) binding to its receptor (EPO- R) have shown that some erythroid cells display a biphasic nature of the ligand-saturation curve, indicating the presence of two classes of binding sites with different affinities. The biochemical basis accounting for this observation is unknown. We found that the culture of a human erythroleukemia cell line with tunicamycin, an inhibitor of N-glycosylation, converted the biphasic Scatchard plot to a single phase with high-affinity sites. Scatchard plots of baby hamster kidney (BHK) cells that had been engineered to express cloned mouse EPO-R were also biphasic and the plots of cells cultured with tunicamycin became a single phase with high-affinity sites. Mouse EPO-R is glycosylated at one asparagine residue in the extracellular region. The mutant EPO-R, in which asparagine residue responsible for N-glycosylation was replaced with glutamine residue, was expressed on BHK cells. Unexpectedly, mutant EPO-R was similar in ligand binding to wild-type EPO-R. BHK cells that expressed mutant EPO-R showed biphasic Scatchard plots that were converted to single-phase plots with only high-affinity sites by tunicamycin treatment. These results indicate that the N- linked sugar of EPO-R is not involved in the manifestation of two classes of binding sites, and that there is a yet unidentified glycoprotein crucial for the ligand-saturation characteristics of EPO-R.

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45

Nagao, M., S. Matsumoto, S. Masuda, and R. Sasaki. "Effect of tunicamycin treatment on ligand binding to the erythropoietin receptor: conversion from two classes of binding sites to a single class." Blood 81, no. 10 (May 15, 1993): 2503–10. http://dx.doi.org/10.1182/blood.v81.10.2503.bloodjournal81102503.

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Scatchard analyses of erythropoietin (EPO) binding to its receptor (EPO- R) have shown that some erythroid cells display a biphasic nature of the ligand-saturation curve, indicating the presence of two classes of binding sites with different affinities. The biochemical basis accounting for this observation is unknown. We found that the culture of a human erythroleukemia cell line with tunicamycin, an inhibitor of N-glycosylation, converted the biphasic Scatchard plot to a single phase with high-affinity sites. Scatchard plots of baby hamster kidney (BHK) cells that had been engineered to express cloned mouse EPO-R were also biphasic and the plots of cells cultured with tunicamycin became a single phase with high-affinity sites. Mouse EPO-R is glycosylated at one asparagine residue in the extracellular region. The mutant EPO-R, in which asparagine residue responsible for N-glycosylation was replaced with glutamine residue, was expressed on BHK cells. Unexpectedly, mutant EPO-R was similar in ligand binding to wild-type EPO-R. BHK cells that expressed mutant EPO-R showed biphasic Scatchard plots that were converted to single-phase plots with only high-affinity sites by tunicamycin treatment. These results indicate that the N- linked sugar of EPO-R is not involved in the manifestation of two classes of binding sites, and that there is a yet unidentified glycoprotein crucial for the ligand-saturation characteristics of EPO-R.

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46

Raborn, Joel, Wei Wang, and Bing-Hao Luo. "Regulation of Integrin αIIbβ3 Ligand Binding and Signaling by the Metal Ion Binding Sites in the β I Domain." Biochemistry 50, no. 12 (March 29, 2011): 2084–91. http://dx.doi.org/10.1021/bi2000092.

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47

Hung, Che-Lun, and Guan-Jie Hua. "Cloud Computing for Protein-Ligand Binding Site Comparison." BioMed Research International 2013 (2013): 1–7. http://dx.doi.org/10.1155/2013/170356.

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The proteome-wide analysis of protein-ligand binding sites and their interactions with ligands is important in structure-based drug design and in understanding ligand cross reactivity and toxicity. The well-known and commonly used software, SMAP, has been designed for 3D ligand binding site comparison and similarity searching of a structural proteome. SMAP can also predict drug side effects and reassign existing drugs to new indications. However, the computing scale of SMAP is limited. We have developed a high availability, high performance system that expands the comparison scale of SMAP. This cloud computing service, called Cloud-PLBS, combines the SMAP and Hadoop frameworks and is deployed on a virtual cloud computing platform. To handle the vast amount of experimental data on protein-ligand binding site pairs, Cloud-PLBS exploits the MapReduce paradigm as a management and parallelizing tool. Cloud-PLBS provides a web portal and scalability through which biologists can address a wide range of computer-intensive questions in biology and drug discovery.

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48

Byrne, Lee J., Ateesh Sidhu, A. Katrine Wallis, Lloyd W. Ruddock, Robert B. Freedman, Mark J. Howard, and Richard A. Williamson. "Mapping of the ligand-binding site on the b′ domain of human PDI: interaction with peptide ligands and the x-linker region." Biochemical Journal 423, no. 2 (September 25, 2009): 209–17. http://dx.doi.org/10.1042/bj20090565.

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PDI (protein disulfide-isomerase) catalyses the formation of native disulfide bonds of secretory proteins in the endoplasmic reticulum. PDI consists of four thioredoxin-like domains, of which two contain redox-active catalytic sites (a and a′), and two do not (b and b′). The b′ domain is primarily responsible for substrate binding, although the nature and specificity of the substrate-binding site is still poorly understood. In the present study, we show that the b′ domain of human PDI is in conformational exchange, but that its structure is stabilized by the addition of peptide ligands or by binding the x-linker region. The location of the ligand-binding site in b′ was mapped by NMR chemical shift perturbation and found to consist primarily of residues from the core β-sheet and α-helices 1 and 3. This site is where the x-linker region binds in the X-ray structure of b′x and we show that peptide ligands can compete with x binding at this site. The finding that x binds in the principal ligand-binding site of b′ further supports the hypothesis that x functions to gate access to this site and so modulates PDI activity.

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FAIRCLOUGH, ROBERT H., ROBERT JOSEPHS, and DAVID P. RICHMAN. "Imaging Ligand Binding Sites on the Torpedo Acetylcholine Receptor." Annals of the New York Academy of Sciences 681, no. 1 Myasthenia Gr (June 1993): 113–25. http://dx.doi.org/10.1111/j.1749-6632.1993.tb22878.x.

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50

Plow, EF, RP McEver, BS Coller, VL Jr Woods, GA Marguerie, and MH Ginsberg. "Related binding mechanisms for fibrinogen, fibronectin, von Willebrand factor, and thrombospondin on thrombin-stimulated human platelets." Blood 66, no. 3 (September 1, 1985): 724–27. http://dx.doi.org/10.1182/blood.v66.3.724.bloodjournal663724.

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Fibrinogen, fibronectin, von Willebrand factor, and thrombospondin are four large glycoproteins that bind to thrombin-stimulated platelets and influence cellular adhesive functions. The effects of five monoclonal antibodies that react with platelet membrane glycoproteins (GP) IIb and/or IIIa on the binding of these four molecules to stimulated platelets were assessed. Tab and PMI-1, antibodies recognizing GPIIb, had no effect, whereas 10E5 and 2G12, antibodies that immunoprecipitate both GPIIb and IIIa in the presence of calcium, inhibited binding of all four ligands by greater than 85%. T10, an antibody specific for the GPIIb-IIIa complex, produced partial inhibition (60% to 80%) of the binding of each ligand. Inhibitory antibodies were effective in the same dose range for all four proteins and also inhibited binding of fibrinogen, fibronectin, and von Willebrand factor to receptors fixed in an induced state (thrombin-stimulated platelets fixed with paraformaldehyde). Thrombospondin did not bind to these fixed cell preparations. The results suggest that these four adhesive proteins have a related mechanism of binding to thrombin-stimulated platelets. This related mechanism may entail the sharing of some, but not necessarily all, binding sites for the four ligands or a proximal relationship between these binding sites.

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Journal articles on the topic 'Binding sites (Biochemistry) Ligand binding (Biochemistry)'

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