View source for 9deq


==Cryo-EM structures of full-length integrin alphaIIbbeta3 in native lipids complexed with modified tirofiban==
<StructureSection load='9deq' size='340' side='right'caption='[[9deq]], [[Resolution|resolution]] 4.10&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[9deq]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=9DEQ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9DEQ 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]] 4.1&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1A5G:N-(1,3-benzoxazole-2-carbonyl)-O-[4-(piperidin-4-yl)butyl]-L-tyrosine'>A1A5G</scene>, <scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=CLR:CHOLESTEROL'>CLR</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</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=9deq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9deq OCA], [https://pdbe.org/9deq PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9deq RCSB], [https://www.ebi.ac.uk/pdbsum/9deq PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9deq 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 ==
Venous thrombosis (VT) is a common vascular disease associated with reduced survival and a high recurrence rate. VT is initiated by the accumulation of platelets and neutrophils at sites of endothelial cell activation. A role for platelet alphaIIbbeta3 in VT is not established, a task complicated by the increased bleeding risk caused by partial agonists such as tirofiban. Here, we show that m-tirofiban, a modified version of tirofiban, does not agonize alphaIIbbeta3 based on lack of neoepitope expression and the cryo-EM structure of m-tirofiban/full-length alphaIIbbeta3 complex. m-tirofiban abolishes agonist-induced platelet aggregation while preserving clot retraction ex vivo and, unlike tirofiban, it suppresses venous thrombogenesis in a mouse model without increasing bleeding. These findings establish a key role for alphaIIbbeta3 in VT initiation and suggest that m-tirofiban and compounds with a similar structurally-defined mechanism of action merit consideration as potential thromboprophylaxis agents in patients at high risk for VT and hemorrhage.

Platelet integrin alphaIIbbeta3 plays a key role in a venous thrombogenesis mouse model.,Adair BD, Field CO, Alonso JL, Xiong JP, Deng SX, Ahn HS, Mashin E, Clish CB, van Agthoven J, Yeager M, Guo Y, Tess DA, Landry DW, Poncz M, Arnaout MA Nat Commun. 2024 Oct 4;15(1):8612. doi: 10.1038/s41467-024-52869-3. PMID:39366965<ref>PMID:39366965</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 9deq" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Adair B]]
[[Category: Arnaout MA]]
[[Category: Xiong JP]]
[[Category: Yeager M]]