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| | <StructureSection load='5thp' size='340' side='right'caption='[[5thp]], [[Resolution|resolution]] 3.01Å' scene=''> | | <StructureSection load='5thp' size='340' side='right'caption='[[5thp]], [[Resolution|resolution]] 3.01Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5thp]] is a 18 chain structure with sequence from [http://en.wikipedia.org/wiki/ ] and [http://en.wikipedia.org/wiki/Calloselasma_rhodostoma Calloselasma rhodostoma]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5THP OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5THP FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5thp]] is a 18 chain structure with sequence from [https://en.wikipedia.org/wiki/Calloselasma_rhodostoma Calloselasma rhodostoma] and [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5THP OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5THP FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.006Å</td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5thp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5thp OCA], [http://pdbe.org/5thp PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5thp RCSB], [http://www.ebi.ac.uk/pdbsum/5thp PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5thp ProSAT]</span></td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=5thp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5thp OCA], [https://pdbe.org/5thp PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5thp RCSB], [https://www.ebi.ac.uk/pdbsum/5thp PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5thp ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/SLEC_CALRH SLEC_CALRH]] Potent inhibitor of collagen-induced platelet aggregation. It acts by binding to the integrin alpha2A domain and blocks collagen binding to integrin alpha-2/beta-1 (ITGA2/ITGB1). The gamma/delta subunits mainly contribute to this activity.<ref>PMID:11121411</ref> <ref>PMID:12871211</ref> [[http://www.uniprot.org/uniprot/ITA2_HUMAN ITA2_HUMAN]] Integrin alpha-2/beta-1 is a receptor for laminin, collagen, collagen C-propeptides, fibronectin and E-cadherin. It recognizes the proline-hydroxylated sequence G-F-P-G-E-R in collagen. It is responsible for adhesion of platelets and other cells to collagens, modulation of collagen and collagenase gene expression, force generation and organization of newly synthesized extracellular matrix. [[http://www.uniprot.org/uniprot/SLED_CALRH SLED_CALRH]] Potent inhibitor of collagen-induced platelet aggregation. It acts by binding to the integrin alpha2A domain and blocks collagen binding to integrin alpha-2/beta-1 (ITGA2/ITGB1). The gamma/delta subunits mainly contribute to this activity.<ref>PMID:11121411</ref> <ref>PMID:12871211</ref> | + | [https://www.uniprot.org/uniprot/SLEC_CALRH SLEC_CALRH] Potent inhibitor of collagen-induced platelet aggregation. It acts by binding to the integrin alpha2A domain and blocks collagen binding to integrin alpha-2/beta-1 (ITGA2/ITGB1). The gamma/delta subunits mainly contribute to this activity.<ref>PMID:11121411</ref> <ref>PMID:12871211</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </StructureSection> | | </StructureSection> |
| | [[Category: Calloselasma rhodostoma]] | | [[Category: Calloselasma rhodostoma]] |
| | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: McDougall, M]] | + | [[Category: McDougall M]] |
| - | [[Category: Orriss, G L]] | + | [[Category: Orriss GL]] |
| - | [[Category: Stetefeld, J]] | + | [[Category: Stetefeld J]] |
| - | [[Category: C-type lectin]]
| + | |
| - | [[Category: Cell adhesion]]
| + | |
| - | [[Category: Coagulation]]
| + | |
| - | [[Category: Integrin]]
| + | |
| - | [[Category: Venom]]
| + | |
| Structural highlights
5thp is a 18 chain structure with sequence from Calloselasma rhodostoma and Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Method: | X-ray diffraction, Resolution 3.006Å |
| Ligands: | , , , , |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
SLEC_CALRH Potent inhibitor of collagen-induced platelet aggregation. It acts by binding to the integrin alpha2A domain and blocks collagen binding to integrin alpha-2/beta-1 (ITGA2/ITGB1). The gamma/delta subunits mainly contribute to this activity.[1] [2]
Publication Abstract from PubMed
The collagen binding integrin alpha2beta1 plays a crucial role in hemostasis, fibrosis, and cancer progression amongst others. It is specifically inhibited by rhodocetin (RC), a C-type lectin-related protein (CLRP) found in Malayan pit viper (Calloselasma rhodostoma) venom. The structure of RC alone reveals a heterotetramer arranged as an alphabeta and gammadelta subunit in a cruciform shape. RC specifically binds to the collagen binding A-domain of the integrin alpha2 subunit, thereby blocking collagen-induced platelet aggregation. However, until now, the molecular basis for this interaction has remained unclear. Here, we present the molecular structure of the RCgammadelta-alpha2A complex solved to 3.0 A resolution. Our findings show that RC undergoes a dramatic structural reorganization upon binding to alpha2beta1 integrin. Besides the release of the nonbinding RCalphabeta tandem, the RCgamma subunit interacts with loop 2 of the alpha2A domain as result of a dramatic conformational change. The RCdelta subunit contacts the integrin alpha2A domain in the "closed" conformation through its helix C. Combined with epitope-mapped antibodies, conformationally locked alpha2A domain mutants, point mutations within the alpha2A loop 2, and chemical modifications of the purified toxin protein, this molecular structure of RCgammadelta-alpha2A complex explains the inhibitory mechanism and specificity of RC for alpha2beta1 integrin.
Dramatic and concerted conformational changes enable rhodocetin to block alpha2beta1 integrin selectively.,Eble JA, McDougall M, Orriss GL, Niland S, Johanningmeier B, Pohlentz G, Meier M, Karrasch S, Estevao-Costa MI, Martins Lima A, Stetefeld J PLoS Biol. 2017 Jul 13;15(7):e2001492. doi: 10.1371/journal.pbio.2001492., eCollection 2017 Jul. PMID:28704364[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Eble JA, Beermann B, Hinz HJ, Schmidt-Hederich A. alpha 2beta 1 integrin is not recognized by rhodocytin but is the specific, high affinity target of rhodocetin, an RGD-independent disintegrin and potent inhibitor of cell adhesion to collagen. J Biol Chem. 2001 Apr 13;276(15):12274-84. Epub 2000 Dec 19. PMID:11121411 doi:http://dx.doi.org/10.1074/jbc.M009338200
- ↑ Eble JA, Tuckwell DS. The alpha2beta1 integrin inhibitor rhodocetin binds to the A-domain of the integrin alpha2 subunit proximal to the collagen-binding site. Biochem J. 2003 Nov 15;376(Pt 1):77-85. PMID:12871211 doi:http://dx.doi.org/10.1042/BJ20030373
- ↑ Eble JA, McDougall M, Orriss GL, Niland S, Johanningmeier B, Pohlentz G, Meier M, Karrasch S, Estevao-Costa MI, Martins Lima A, Stetefeld J. Dramatic and concerted conformational changes enable rhodocetin to block alpha2beta1 integrin selectively. PLoS Biol. 2017 Jul 13;15(7):e2001492. doi: 10.1371/journal.pbio.2001492., eCollection 2017 Jul. PMID:28704364 doi:http://dx.doi.org/10.1371/journal.pbio.2001492
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