View source for 9dao


==AlphaIIbbeta3 in fully-extended conformation in complex with R6H8 Fab==
<StructureSection load='9dao' size='340' side='right'caption='[[9dao]], [[Resolution|resolution]] 2.80&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[9dao]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=9DAO OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9DAO 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=9dao FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9dao OCA], [https://pdbe.org/9dao PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9dao RCSB], [https://www.ebi.ac.uk/pdbsum/9dao PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9dao 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 ==
To produce a murine monoclonal antibody that binds to alphaIIbbeta3 and inhibits clot retraction (CR) we immunized mice with human platelets and tested hybridoma supernatants for their ability to bind to alphaIIbbeta3 and inhibit CR. The IgG1 mAb R6H8 completely inhibited CR at 20 microg/ml. Paradoxically, 5 microg/ml R6H8 initiated platelet aggregation and induced P-selectin expression, fibrinogen binding, and PAC-1 binding. At 20 microg/ml, however, R6H8 completely inhibited aggregation induced by peptide SFLLRN (25 microg/ml; T6) and T6-induced fibrinogen and PAC-1 binding to platelets. Platelet aggregation induced by R6H8 was inhibited by mAb IV.3, which blocks the FcgammaIIa receptor (FcgammaRIIa), and the Fab fragment of R6H8 did not induce platelet aggregation, suggesting that R6H8 binds to both alphaIIbbeta3 and FcgammaRIIa. Cryo-EM analysis of the R6H8 Fab-alphaIIbbeta3 complex revealed that R6H8: 1) Binds to the alphaIIbbeta3 RGD binding pocket via an RYD sequence in its heavy chain CDR3, 2) Interacts with beta3 Asp126, producing a reorientation of Asp126 and loss of the ADMIDAS Ca2+, and 3) Initiates swing-out of the beta3 hybrid domain. We conclude that R6H8 is an alphaIIbbeta3 ligand-mimetic mAb that activates platelets via FcgammaRIIa at low concentrations and potently inhibits platelet aggregation and clot retraction at high concentrations. R6H8 simulates the actions of a number of pathological antibodies, including platelet-activating antibodies developed after therapy with glycoprotein IIb/IIIa (alphaIIbbeta3) inhibitors and platelet-activating antibodies in heparin-induced thrombocytopenia and vaccine-induced immune thrombotic thrombocytopenia. As such, it may be a valuable reagent for better understanding these disorders and identifying potential therapies.

An alphaIIbbeta3 Ligand-Mimetic Murine Monoclonal Antibody That Produces Platelet Activation by Engaging the FcgammaIIa Receptor.,Wang J, Buitrago L, Wang L, Li J, Walz T, Coller BS Blood Adv. 2025 Mar 18:bloodadvances.2024015368. doi: , 10.1182/bloodadvances.2024015368. PMID:40101235<ref>PMID:40101235</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 9dao" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Mus musculus]]
[[Category: Buitrago L]]
[[Category: Coller BS]]
[[Category: Li JH]]
[[Category: Walz T]]
[[Category: Wang JL]]
[[Category: Wang L]]