6v4p: Difference between revisions

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-'''Unreleased structure'''
-The entry 6v4p is ON HOLD  until Paper Publication
+==Structure of the integrin AlphaIIbBeta3-Abciximab complex==
+<SX load='6v4p' size='340' side='right' viewer='molstar' caption='[[6v4p]], [[Resolution|resolution]] 2.80&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[6v4p]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6V4P OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6V4P FirstGlance]. <br>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 2.8&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6v4p FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6v4p OCA], [https://pdbe.org/6v4p PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6v4p RCSB], [https://www.ebi.ac.uk/pdbsum/6v4p PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6v4p ProSAT]</span></td></tr>
+</table>
+== Disease ==
+[https://www.uniprot.org/uniprot/ITA2B_HUMAN ITA2B_HUMAN] Defects in ITGA2B are a cause of Glanzmann thrombasthenia (GT) [MIM:[https://omim.org/entry/273800 273800]; also known as thrombasthenia of Glanzmann and Naegeli. GT is the most common inherited disease of platelets. It is an autosomal recessive disorder characterized by mucocutaneous bleeding of mild-to-moderate severity and the inability of this integrin to recognize macromolecular or synthetic peptide ligands. GT has been classified clinically into types I and II. In type I, platelets show absence of the glycoprotein IIb/beta-3 complexes at their surface and lack fibrinogen and clot retraction capability. In type II, the platelets express the glycoprotein IIb/beta-3 complex at reduced levels (5-20% controls), have detectable amounts of fibrinogen, and have low or moderate clot retraction capability. The platelets of GT 'variants' have normal or near normal (60-100%) expression of dysfunctional receptors.<ref>PMID:8282784</ref> <ref>PMID:7508443</ref> <ref>PMID:7706461</ref> <ref>PMID:8704171</ref> <ref>PMID:9215749</ref> <ref>PMID:9473221</ref> <ref>PMID:9763559</ref> <ref>PMID:9722314</ref> <ref>PMID:9734640</ref> <ref>PMID:9920835</ref> <ref>PMID:10607701</ref> <ref>PMID:11798398</ref> <ref>PMID:12181054</ref> <ref>PMID:12083483</ref> <ref>PMID:12424194</ref> <ref>PMID:12506038</ref> <ref>PMID:15099289</ref> <ref>PMID:15219201</ref> <ref>PMID:17018384</ref>
+== Function ==
+[https://www.uniprot.org/uniprot/ITA2B_HUMAN ITA2B_HUMAN] Integrin alpha-IIb/beta-3 is a receptor for fibronectin, fibrinogen, plasminogen, prothrombin, thrombospondin and vitronectin. It recognizes the sequence R-G-D in a wide array of ligands. It recognizes the sequence H-H-L-G-G-G-A-K-Q-A-G-D-V in fibrinogen gamma chain. Following activation integrin alpha-IIb/beta-3 brings about platelet/platelet interaction through binding of soluble fibrinogen. This step leads to rapid platelet aggregation which physically plugs ruptured endothelial cell surface.
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+OBJECTIVE: The alphaIIbbeta3 antagonist antiplatelet drug abciximab is the chimeric antigen-binding fragment comprising the variable regions of murine monoclonal antibody 7E3 and the constant domains of human IgG1 and light chain kappa. Previous mutagenesis studies suggested that abciximab binds to the beta3 C177-C184 specificity-determining loop (SDL) and Trp129 on the adjacent beta1-alpha1 helix. These studies could not, however, assess whether 7E3 or abciximab prevents fibrinogen binding by steric interference, disruption of either the alphaIIbbeta3-binding pocket for fibrinogen or the beta3 SDL (which is not part of the binding pocket but affects fibrinogen binding), or some combination of these effects. To address this gap, we used cryo-electron microscopy to determine the structure of the alphaIIbbeta3-abciximab complex at 2.8 A resolution. Approach and Results: The interacting surface of abciximab is comprised of residues from all 3 complementarity-determining regions of both the light and heavy chains, with high representation of aromatic residues. Binding is primarily to the beta3 SDL and neighboring residues, the beta1-alpha1 helix, and beta3 residues Ser211, Val212 and Met335. Unexpectedly, the structure also indicated several interactions with alphaIIb. As judged by the cryo-electron microscopy model, molecular-dynamics simulations, and mutagenesis, the binding of abciximab does not appear to rely on the interaction with the alphaIIb residues and does not result in disruption of the fibrinogen-binding pocket; it does, however, compress and reduce the flexibility of the SDL. CONCLUSIONS: We deduce that abciximab prevents ligand binding by steric interference, with a potential contribution via displacement of the SDL and limitation of the flexibility of the SDL residues.
-Authors:
+Cryo-Electron Microscopy Structure of the alphaIIbbeta3-Abciximab Complex.,Nesic D, Zhang Y, Spasic A, Li J, Provasi D, Filizola M, Walz T, Coller BS Arterioscler Thromb Vasc Biol. 2020 Jan 23:ATVBAHA119313671. doi:, 10.1161/ATVBAHA.119.313671. PMID:31969014<ref>PMID:31969014</ref>
-Description:
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
+<div class="pdbe-citations 6v4p" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Integrin 3D structures|Integrin 3D structures]]
+*[[Monoclonal Antibodies 3D structures|Monoclonal Antibodies 3D structures]]
+== References ==
+<references/>
+__TOC__
+</SX>
+[[Category: Homo sapiens]]
+[[Category: Large Structures]]
+[[Category: Synthetic construct]]
+[[Category: Coller BS]]
+[[Category: Filizola M]]
+[[Category: Li J]]
+[[Category: Nesic D]]
+[[Category: Provasi D]]
+[[Category: Spasic A]]
+[[Category: Walz T]]
+[[Category: Zhang Y]]