View source for 4mmz


==Integrin AlphaVBeta3 ectodomain bound to an antagonistic tenth domain of Fibronectin==
<StructureSection load='4mmz' size='340' side='right'caption='[[4mmz]], [[Resolution|resolution]] 3.10&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4mmz]] is a 3 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=4MMZ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4MMZ FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.1&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene>, <scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</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=4mmz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4mmz OCA], [https://pdbe.org/4mmz PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4mmz RCSB], [https://www.ebi.ac.uk/pdbsum/4mmz PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4mmz ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/ITAV_HUMAN ITAV_HUMAN] The alpha-V integrins are receptors for vitronectin, cytotactin, fibronectin, fibrinogen, laminin, matrix metalloproteinase-2, osteopontin, osteomodulin, prothrombin, thrombospondin and vWF. They recognize the sequence R-G-D in a wide array of ligands. In case of HIV-1 infection, the interaction with extracellular viral Tat protein seems to enhance angiogenesis in Kaposi's sarcoma lesions.
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== Publication Abstract from PubMed ==
Integrins are important therapeutic targets. However, current RGD-based anti-integrin drugs are also partial agonists, inducing conformational changes that trigger potentially fatal immune reactions and paradoxical cell adhesion. Here we describe the first crystal structure of alphaVbeta3 bound to a physiologic ligand, the tenth type III RGD domain of wild-type fibronectin (wtFN10), or to a high-affinity mutant (hFN10) shown here to act as a pure antagonist. Comparison of these structures revealed a central pi-pi interaction between Trp1496 in the RGD-containing loop of hFN10 and Tyr122 of the beta3 subunit that blocked conformational changes triggered by wtFN10 and trapped hFN10-bound alphaVbeta3 in an inactive conformation. Removing the Trp1496 or Tyr122 side chains or reorienting Trp1496 away from Tyr122 converted hFN10 into a partial agonist. These findings offer new insights into the mechanism of integrin activation and a basis for the design of RGD-based pure antagonists.

Structural basis for pure antagonism of integrin alphaVbeta3 by a high-affinity form of fibronectin.,Van Agthoven JF, Xiong JP, Alonso JL, Rui X, Adair BD, Goodman SL, Arnaout MA Nat Struct Mol Biol. 2014 Apr;21(4):383-8. doi: 10.1038/nsmb.2797. Epub 2014 Mar , 23. PMID:24658351<ref>PMID:24658351</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 4mmz" style="background-color:#fffaf0;"></div>

==See Also==
*[[Fibronectin 3D structures|Fibronectin 3D structures]]
*[[Integrin 3D structures|Integrin 3D structures]]
== References ==
<references/>
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Arnaout MA]]
[[Category: Xiong J]]
[[Category: Van Agthoven J]]