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==New structural insights on short disintegrin echistatin by NMR==
==New structural insights on short disintegrin echistatin by NMR==
<StructureSection load='1ro3' size='340' side='right'caption='[[1ro3]], [[NMR_Ensembles_of_Models | 20 NMR models]]' scene=''>
<StructureSection load='1ro3' size='340' side='right'caption='[[1ro3]]' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[1ro3]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Echis_carinatus Echis carinatus]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1RO3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1RO3 FirstGlance]. <br>
<table><tr><td colspan='2'>[[1ro3]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Echis_carinatus Echis carinatus]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1RO3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1RO3 FirstGlance]. <br>
</td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[2ech|2ech]]</div></td></tr>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Solution NMR</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=1ro3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1ro3 OCA], [https://pdbe.org/1ro3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1ro3 RCSB], [https://www.ebi.ac.uk/pdbsum/1ro3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1ro3 ProSAT]</span></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=1ro3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1ro3 OCA], [https://pdbe.org/1ro3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1ro3 RCSB], [https://www.ebi.ac.uk/pdbsum/1ro3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1ro3 ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== Function ==
[[https://www.uniprot.org/uniprot/VM2EA_ECHCS VM2EA_ECHCS]] Potent inhibitor of ligand binding to the integrins alpha-V/beta-3 (ITGAV/ITGB3), alpha-5/beta-1 (ITGA5/ITGB1) and alpha-IIb/beta-3 (ITGA2B/ITGB3). Competition with fibrinogen for the RGD recognition sites on the alpha-IIb/beta-3 integrin (glyco-protein IIb/IIIa complex) results in the inhibition of platelet aggregation and other antithrombotic properties such as an ability to prevent coronary thrombosis in animal models. Is also a potent inhibitor of bone resorption. This results from the blocking of the interaction of alpha-V/beta-3 integrin on the surface of osteoclasts with bone extracellular matrix. In addition, interaction with alpha-V/beta-3 also inhibits adhesion of human umbilical vein endothelial cells (HUVEC) to immobilized vitronectin and fibronectin.<ref>PMID:2320569</ref> <ref>PMID:3198653</ref> <ref>PMID:9269775</ref>
[https://www.uniprot.org/uniprot/VM2EA_ECHCS VM2EA_ECHCS] Potent inhibitor of ligand binding to the integrins alpha-V/beta-3 (ITGAV/ITGB3), alpha-5/beta-1 (ITGA5/ITGB1) and alpha-IIb/beta-3 (ITGA2B/ITGB3). Competition with fibrinogen for the RGD recognition sites on the alpha-IIb/beta-3 integrin (glyco-protein IIb/IIIa complex) results in the inhibition of platelet aggregation and other antithrombotic properties such as an ability to prevent coronary thrombosis in animal models. Is also a potent inhibitor of bone resorption. This results from the blocking of the interaction of alpha-V/beta-3 integrin on the surface of osteoclasts with bone extracellular matrix. In addition, interaction with alpha-V/beta-3 also inhibits adhesion of human umbilical vein endothelial cells (HUVEC) to immobilized vitronectin and fibronectin.<ref>PMID:2320569</ref> <ref>PMID:3198653</ref> <ref>PMID:9269775</ref>  
== Evolutionary Conservation ==
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
[[Image:Consurf_key_small.gif|200px|right]]
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</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=1ro3 ConSurf].
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=1ro3 ConSurf].
<div style="clear:both"></div>
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Echistatin is a potent antagonist of the integrins alpha(v)beta3, alpha5beta1 and alpha(IIb)beta3. Its full inhibitory activity depends on an RGD (Arg-Gly-Asp) motif expressed at the tip of the integrin-binding loop and on its C-terminal tail. Previous NMR structures of echistatin showed a poorly defined integrin-recognition sequence and an incomplete C-terminal tail, which left the molecular basis of the functional synergy between the RGD loop and the C-terminal region unresolved. We report a high-resolution structure of echistatin and an analysis of its internal motions by off-resonance ROESY (rotating-frame Overhauser enhancement spectroscopy). The full-length C-terminal polypeptide is visible as a beta-hairpin running parallel to the RGD loop and exposing at the tip residues Pro43, His44 and Lys45. The side chains of the amino acids of the RGD motif have well-defined conformations. The integrin-binding loop displays an overall movement with maximal amplitude of 30 degrees . Internal angular motions in the 100-300 ps timescale indicate increased flexibility for the backbone atoms at the base of the integrin-recognition loop. In addition, backbone atoms of the amino acids Ala23 (flanking the R24GD26 tripeptide) and Asp26 of the integrin-binding motif showed increased angular mobility, suggesting the existence of major and minor hinge effects at the base and the tip, respectively, of the RGD loop. A strong network of NOEs (nuclear Overhauser effects) between residues of the RGD loop and the C-terminal tail indicate concerted motions between these two functional regions. A full-length echistatin-alpha(v)beta3 docking model suggests that echistatin's C-terminal amino acids may contact alpha(v)-subunit residues and provides new insights to delineate structure-function correlations.
Conformation and concerted dynamics of the integrin-binding site and the C-terminal region of echistatin revealed by homonuclear NMR.,Monleon D, Esteve V, Kovacs H, Calvete JJ, Celda B Biochem J. 2005 Apr 1;387(Pt 1):57-66. PMID:15535803<ref>PMID:15535803</ref>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 1ro3" style="background-color:#fffaf0;"></div>


==See Also==
==See Also==
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[[Category: Echis carinatus]]
[[Category: Echis carinatus]]
[[Category: Large Structures]]
[[Category: Large Structures]]
[[Category: Calvete, J J]]
[[Category: Calvete JJ]]
[[Category: Celda, B]]
[[Category: Celda B]]
[[Category: Esteve, V]]
[[Category: Esteve V]]
[[Category: Marcinkiewicz, C]]
[[Category: Marcinkiewicz C]]
[[Category: Monleon, D]]
[[Category: Monleon D]]
[[Category: Cell adhesion]]
[[Category: No regular secondary structure]]

Latest revision as of 11:25, 1 May 2024

New structural insights on short disintegrin echistatin by NMRNew structural insights on short disintegrin echistatin by NMR

Structural highlights

1ro3 is a 1 chain structure with sequence from Echis carinatus. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:Solution NMR
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

VM2EA_ECHCS Potent inhibitor of ligand binding to the integrins alpha-V/beta-3 (ITGAV/ITGB3), alpha-5/beta-1 (ITGA5/ITGB1) and alpha-IIb/beta-3 (ITGA2B/ITGB3). Competition with fibrinogen for the RGD recognition sites on the alpha-IIb/beta-3 integrin (glyco-protein IIb/IIIa complex) results in the inhibition of platelet aggregation and other antithrombotic properties such as an ability to prevent coronary thrombosis in animal models. Is also a potent inhibitor of bone resorption. This results from the blocking of the interaction of alpha-V/beta-3 integrin on the surface of osteoclasts with bone extracellular matrix. In addition, interaction with alpha-V/beta-3 also inhibits adhesion of human umbilical vein endothelial cells (HUVEC) to immobilized vitronectin and fibronectin.[1] [2] [3]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

See Also

References

  1. ↑ Dennis MS, Henzel WJ, Pitti RM, Lipari MT, Napier MA, Deisher TA, Bunting S, Lazarus RA. Platelet glycoprotein IIb-IIIa protein antagonists from snake venoms: evidence for a family of platelet-aggregation inhibitors. Proc Natl Acad Sci U S A. 1990 Apr;87(7):2471-5. PMID:2320569
  2. ↑ Gan ZR, Gould RJ, Jacobs JW, Friedman PA, Polokoff MA. Echistatin. A potent platelet aggregation inhibitor from the venom of the viper, Echis carinatus. J Biol Chem. 1988 Dec 25;263(36):19827-32. PMID:3198653
  3. ↑ Marcinkiewicz C, Vijay-Kumar S, McLane MA, Niewiarowski S. Significance of RGD loop and C-terminal domain of echistatin for recognition of alphaIIb beta3 and alpha(v) beta3 integrins and expression of ligand-induced binding site. Blood. 1997 Aug 15;90(4):1565-75. PMID:9269775
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