4g1m: Difference between revisions

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<StructureSection load='4g1m' size='340' side='right'caption='[[4g1m]], [[Resolution|resolution]] 2.90&Aring;' scene=''>
<StructureSection load='4g1m' size='340' side='right'caption='[[4g1m]], [[Resolution|resolution]] 2.90&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[4g1m]] is a 2 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=4G1M OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4G1M FirstGlance]. <br>
<table><tr><td colspan='2'>[[4g1m]] 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=4G1M OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4G1M FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr>
</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=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3ije|3ije]], [[4g1e|4g1e]]</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=4g1m FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4g1m OCA], [https://pdbe.org/4g1m PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4g1m RCSB], [https://www.ebi.ac.uk/pdbsum/4g1m PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4g1m ProSAT]</span></td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ITGAV, MSK8, VNRA ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), ITGB3, GP3A ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4g1m FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4g1m OCA], [http://pdbe.org/4g1m PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4g1m RCSB], [http://www.ebi.ac.uk/pdbsum/4g1m PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4g1m ProSAT]</span></td></tr>
</table>
</table>
== Disease ==
[[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> 
== Function ==
== Function ==
[[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/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.  
[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 ==
== Publication Abstract from PubMed ==
We determined the crystal structure of 1TM-alphaVbeta3, which represents the complete unconstrained ectodomain plus short C-terminal transmembrane stretches of the alphaV and beta3 subunits. 1TM-alphaVbeta3 is more compact and less active in solution when compared with DeltaTM-alphaVbeta3, which lacks the short C-terminal stretches. The structure reveals a bent conformation and defines the alpha-beta interface between IE2 (EGF-like 2) and the thigh domains. Modifying this interface by site-directed mutagenesis leads to robust integrin activation. Fluorescent lifetime imaging microscopy of inactive full-length alphaVbeta3 on live cells yields a donor-membrane acceptor distance, which is consistent with the bent conformation and does not change in the activated integrin. These data are the first direct demonstration of conformational coupling of the integrin leg and head domains, identify the IE2-thigh interface as a critical steric barrier in integrin activation, and suggest that inside-out activation in intact cells may involve conformational changes other than the postulated switch to a genu-linear state.
Many questions about the significance of structural features of integrin alpha(V)beta(3) with respect to its mechanism of activation remain. We have determined and re-refined crystal structures of the alpha(V)beta(3) ectodomain linked to C-terminal coiled coils (alpha(V)beta(3)-AB) and four transmembrane (TM) residues in each subunit (alpha(V)beta(3)-1TM), respectively. The alpha(V) and beta(3) subunits with four and eight extracellular domains, respectively, are bent at knees between the integrin headpiece and lower legs, and the headpiece has the closed, low-affinity conformation. The structures differ in the occupancy of three metal-binding sites in the betaI domain. Occupancy appears to be related to the pH of crystallization, rather than to the physiologic regulation of ligand binding at the central, metal ion-dependent adhesion site. No electron density was observed for TM residues and much of the alpha(V) linker. alpha(V)beta(3)-AB and alpha(V)beta(3)-1TM demonstrate flexibility in the linker between their extracellular and TM domains, rather than the previously proposed rigid linkage. A previously postulated interface between the alpha(V) and beta(3) subunits at their knees was also not supported, because it lacks high-quality density, required rebuilding in alpha(V)beta(3)-1TM, and differed markedly between alpha(V)beta(3)-1TM and alpha(V)beta(3)-AB. Together with the variation in domain-domain orientation within their bent ectodomains between alpha(V)beta(3)-AB and alpha(V)beta(3)-1TM, these findings are compatible with the requirement for large structural changes, such as extension at the knees and headpiece opening, in conveying activation signals between the extracellular ligand-binding site and the cytoplasm.


Crystal structure of the complete integrin alphaVbeta3 ectodomain plus an alpha/beta transmembrane fragment.,Xiong JP, Mahalingham B, Alonso JL, Borrelli LA, Rui X, Anand S, Hyman BT, Rysiok T, Muller-Pompalla D, Goodman SL, Arnaout MA J Cell Biol. 2009 Aug 24;186(4):589-600. PMID:19704023<ref>PMID:19704023</ref>
alpha(V)beta(3) Integrin Crystal Structures and Their Functional Implications.,Dong X, Mi LZ, Zhu J, Wang W, Hu P, Luo BH, Springer TA Biochemistry. 2012 Nov 6;51(44):8814-28. doi: 10.1021/bi300734n. Epub 2012 Oct, 29. PMID:23106217<ref>PMID:23106217</ref>


From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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==See Also==
==See Also==
*[[Integrin|Integrin]]
*[[Integrin 3D structures|Integrin 3D structures]]
== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Human]]
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Large Structures]]
[[Category: Mi, L]]
[[Category: Mi L]]
[[Category: Springer, T A]]
[[Category: Springer TA]]
[[Category: Zhu, J]]
[[Category: Zhu J]]
[[Category: Protein binding]]

Revision as of 20:20, 19 October 2022

Re-refinement of alpha V beta 3 structure

4g1m, resolution 2.90Å

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