9axl

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Current revision (07:33, 27 November 2024) (edit) (undo)
 
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'''Unreleased structure'''
 
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The entry 9axl is ON HOLD until Paper Publication
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==Structure of the semi-extended AlphaIIbBeta3 in complex with R21D10 Fab==
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<StructureSection load='9axl' size='340' side='right'caption='[[9axl]], [[Resolution|resolution]] 3.30&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[9axl]] 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=9AXL OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9AXL FirstGlance]. <br>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 3.3&#8491;</td></tr>
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<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>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=9axl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9axl OCA], [https://pdbe.org/9axl PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9axl RCSB], [https://www.ebi.ac.uk/pdbsum/9axl PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9axl ProSAT]</span></td></tr>
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</table>
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== Disease ==
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[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>
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== Function ==
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[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.
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Monoclonal antibodies (mAbs) have provided valuable information regarding the structure and function of platelet alphaIIbbeta3. Protein disulfide isomerase (PDI) has been implicated in alphaIIbbeta3 activation and binds to thrombin-activated alphaIIbbeta3. Using human platelets as the immunogen, we identified a new mAb (R21D10) that inhibits the binding of PDI to platelets activated with thrombin receptor-activating peptide (T6). R21D10 also partially inhibited T6-induced fibrinogen and PAC-1 binding to platelets, as well as T6- and adenosine 5'-diphosphate-induced platelet aggregation. Mutual competition experiments showed that R21D10 does not inhibit the binding of mAbs 10E5 (anti-alphaIIb cap domain) or 7E3 (anti-beta3 beta-I domain), and immunoblot studies indicated that R21D10 binds to beta3. The dissociation of alphaIIbbeta3 by EDTA had a minimal effect on R21D10 binding. Cryogenic electron microscopy of the alphaIIbbeta3-R21D10 Fab complex revealed that R21D10 binds to the beta3 integrin-epidermal growth factor 1 (I-EGF1) domain and traps an intermediate conformation of alphaIIbbeta3 with semiextended leg domains. The binding of R21D10 produces a major structural change in the beta3 I-EGF2 domain associated with a new interaction between the beta3 I-EGF2 and alphaIIb thigh domains, which may prevent the swing-out motion of the beta3 hybrid domain required for high-affinity ligand binding and protect alphaIIbbeta3 from EDTA-induced dissociation. R21D10 partially reversed the ligand binding priming effect of eptifibatide, suggesting that it could convert the swung-out conformation into a semiextended conformation. We concluded that R21D10 inhibits ligand binding to alphaIIbbeta3 via a unique allosteric mechanism, which may or may not be related to its inhibition of PDI binding.
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Authors:
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An alphaIIbbeta3 monoclonal antibody traps a semiextended conformation and allosterically inhibits large ligand binding.,Wang L, Wang J, Li J, Walz T, Coller BS Blood Adv. 2024 Aug 27;8(16):4398-4409. doi: 10.1182/bloodadvances.2024013177. PMID:38968144<ref>PMID:38968144</ref>
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Description:
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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[[Category: Unreleased Structures]]
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</div>
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<div class="pdbe-citations 9axl" style="background-color:#fffaf0;"></div>
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== References ==
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<references/>
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__TOC__
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</StructureSection>
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[[Category: Homo sapiens]]
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[[Category: Large Structures]]
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[[Category: Mus musculus]]
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[[Category: Coller B]]
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[[Category: Li JH]]
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[[Category: Walz T]]
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[[Category: Wang JL]]
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[[Category: Wang L]]

Current revision

Structure of the semi-extended AlphaIIbBeta3 in complex with R21D10 Fab

PDB ID 9axl

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