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4mmx

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==Integrin AlphaVBeta3 ectodomain bound to the tenth domain of Fibronectin==
==Integrin AlphaVBeta3 ectodomain bound to the tenth domain of Fibronectin==
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<StructureSection load='4mmx' size='340' side='right' caption='[[4mmx]], [[Resolution|resolution]] 3.32&Aring;' scene=''>
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<StructureSection load='4mmx' size='340' side='right'caption='[[4mmx]], [[Resolution|resolution]] 3.32&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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[[4mmx]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4MMX OCA]. <br>
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<table><tr><td colspan='2'>[[4mmx]] 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=4MMX OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4MMX FirstGlance]. <br>
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<b>[[Ligand|Ligands:]]</b> <scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene><br>
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</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=MAN:ALPHA-D-MANNOSE'>MAN</scene>, <scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr>
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<b>[[Related_structure|Related:]]</b> [[1jv2|1jv2]], [[1l5g|1l5g]], [[3ije|3ije]], [[4g1m|4g1m]], [[4g1e|4g1e]], [[4mmy|4mmy]], [[4mmz|4mmz]]<br>
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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=4mmx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4mmx OCA], [https://pdbe.org/4mmx PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4mmx RCSB], [https://www.ebi.ac.uk/pdbsum/4mmx PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4mmx ProSAT]</span></td></tr>
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<b>Activity:</b> <span class='plainlinks'>[http://en.wikipedia.org/wiki/Glucokinase Glucokinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.1.2 2.7.1.2] </span><br>
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</table>
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<b>Resources:</b> <span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4mmx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4mmx OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4mmx RCSB], [http://www.ebi.ac.uk/pdbsum/4mmx PDBsum]</span><br>
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== Disease ==
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[[http://www.uniprot.org/uniprot/FINC_HUMAN FINC_HUMAN]] Defects in FN1 are the cause of glomerulopathy with fibronectin deposits type 2 (GFND2) [MIM:[http://omim.org/entry/601894 601894]]; also known as familial glomerular nephritis with fibronectin deposits or fibronectin glomerulopathy. GFND is a genetically heterogeneous autosomal dominant disorder characterized clinically by proteinuria, microscopic hematuria, and hypertension that leads to end-stage renal failure in the second to fifth decade of life.<ref>PMID:18268355</ref> [[http://www.uniprot.org/uniprot/ITB3_HUMAN ITB3_HUMAN]] Defects in ITGB3 are a cause of Glanzmann thrombasthenia (GT) [MIM:[http://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:2392682</ref> <ref>PMID:1371279</ref> <ref>PMID:1602006</ref> <ref>PMID:1438206</ref> <ref>PMID:8781422</ref> <ref>PMID:9376589</ref> <ref>PMID:9215749</ref> <ref>PMID:9790984</ref> <ref>PMID:9684783</ref> <ref>PMID:10233432</ref> <ref>PMID:11588040</ref> <ref>PMID:11897046</ref> <ref>PMID:12083483</ref> <ref>PMID:12353082</ref> <ref>PMID:15583747</ref> <ref>PMID:15634267</ref> <ref>PMID:15748237</ref>
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== Function ==
== Function ==
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[[http://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. [[http://www.uniprot.org/uniprot/FINC_HUMAN FINC_HUMAN]] Fibronectins bind cell surfaces and various compounds including collagen, fibrin, heparin, DNA, and actin. Fibronectins are involved in cell adhesion, cell motility, opsonization, wound healing, and maintenance of cell shape.<ref>PMID:8114919</ref> <ref>PMID:11209058</ref> <ref>PMID:15665290</ref> <ref>PMID:19379667</ref> Anastellin binds fibronectin and induces fibril formation. This fibronectin polymer, named superfibronectin, exhibits enhanced adhesive properties. Both anastellin and superfibronectin inhibit tumor growth, angiogenesis and metastasis. Anastellin activates p38 MAPK and inhibits lysophospholipid signaling.<ref>PMID:8114919</ref> <ref>PMID:11209058</ref> <ref>PMID:15665290</ref> <ref>PMID:19379667</ref> [[http://www.uniprot.org/uniprot/ITB3_HUMAN ITB3_HUMAN]] Integrin alpha-V/beta-3 is a receptor for cytotactin, fibronectin, laminin, matrix metalloproteinase-2, osteopontin, osteomodulin, prothrombin, thrombospondin, vitronectin and von Willebrand factor. Integrin alpha-IIb/beta-3 is a receptor for fibronectin, fibrinogen, plasminogen, prothrombin, thrombospondin and vitronectin. Integrins alpha-IIb/beta-3 and alpha-V/beta-3 recognize the sequence R-G-D in a wide array of ligands. Integrin alpha-IIb/beta-3 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 surface. 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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[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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<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
== 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.
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.
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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>
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>
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 4mmx" style="background-color:#fffaf0;"></div>
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==See Also==
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*[[Fibronectin 3D structures|Fibronectin 3D structures]]
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*[[Integrin 3D structures|Integrin 3D structures]]
== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Human]]
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[[Category: Homo sapiens]]
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[[Category: Agthoven, J van.]]
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[[Category: Large Structures]]
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[[Category: Arnaout, M A.]]
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[[Category: Arnaout MA]]
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[[Category: Xiong, J.]]
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[[Category: Xiong J]]
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[[Category: A domain]]
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[[Category: Van Agthoven J]]
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[[Category: Beta propeller]]
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[[Category: Beta ta thigh]]
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[[Category: Cell adhesion]]
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[[Category: Egf repeat]]
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[[Category: Fibronectin]]
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[[Category: Hybrid domain]]
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[[Category: Integrin]]
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[[Category: Psi]]
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[[Category: Rgd motif]]
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[[Category: Vitronectin]]
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Current revision

Integrin AlphaVBeta3 ectodomain bound to the tenth domain of Fibronectin

PDB ID 4mmx

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