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| | ==Crystal structure of the human thromboxane A2 receptor bound to daltroban== | | ==Crystal structure of the human thromboxane A2 receptor bound to daltroban== |
| - | <StructureSection load='6iiv' size='340' side='right' caption='[[6iiv]], [[Resolution|resolution]] 3.00Å' scene=''> | + | <StructureSection load='6iiv' size='340' side='right'caption='[[6iiv]], [[Resolution|resolution]] 3.00Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6iiv]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/"bacillus_coli"_migula_1895 "bacillus coli" migula 1895]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6IIV OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6IIV FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6iiv]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Clostridium_pasteurianum Clostridium pasteurianum], [https://en.wikipedia.org/wiki/Escherichia_coli Escherichia coli] 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=6IIV OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6IIV FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=A90:2-[4-[2-[(4-chlorophenyl)sulfonylamino]ethyl]phenyl]ethanoic+acid'>A90</scene>, <scene name='pdbligand=CLR:CHOLESTEROL'>CLR</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</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]] 3Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">TBXA2R ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=562 "Bacillus coli" Migula 1895])</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A90:2-[4-[2-[(4-chlorophenyl)sulfonylamino]ethyl]phenyl]ethanoic+acid'>A90</scene>, <scene name='pdbligand=CLR:CHOLESTEROL'>CLR</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></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=6iiv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6iiv OCA], [http://pdbe.org/6iiv PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6iiv RCSB], [http://www.ebi.ac.uk/pdbsum/6iiv PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6iiv 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=6iiv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6iiv OCA], [https://pdbe.org/6iiv PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6iiv RCSB], [https://www.ebi.ac.uk/pdbsum/6iiv PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6iiv ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | + | == Disease == |
| | + | [https://www.uniprot.org/uniprot/TA2R_HUMAN TA2R_HUMAN] Bleeding diathesis due to thromboxane synthesis deficiency. Disease susceptibility is associated with variants affecting the gene represented in this entry. |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/C562_ECOLX C562_ECOLX]] Electron-transport protein of unknown function. | + | [https://www.uniprot.org/uniprot/C562_ECOLX C562_ECOLX] Electron-transport protein of unknown function.[https://www.uniprot.org/uniprot/TA2R_HUMAN TA2R_HUMAN] Receptor for thromboxane A2 (TXA2), a potent stimulator of platelet aggregation. The activity of this receptor is mediated by a G-protein that activates a phosphatidylinositol-calcium second messenger system. In the kidney, the binding of TXA2 to glomerular TP receptors causes intense vasoconstriction. Activates phospholipase C.<ref>PMID:8613548</ref> Activates adenylyl cyclase.<ref>PMID:8613548</ref> Inhibits adenylyl cyclase.<ref>PMID:8613548</ref> [https://www.uniprot.org/uniprot/RUBR_CLOPA RUBR_CLOPA] Rubredoxin is a small nonheme, iron protein lacking acid-labile sulfide. Its single Fe, chelated to 4 Cys, functions as an electron acceptor and may also stabilize the conformation of the molecule. |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Bacillus coli migula 1895]] | + | [[Category: Clostridium pasteurianum]] |
| - | [[Category: Fan, H]] | + | [[Category: Escherichia coli]] |
| - | [[Category: Wu, B]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Zhao, Q]] | + | [[Category: Large Structures]] |
| - | [[Category: Antagonist]] | + | [[Category: Fan H]] |
| - | [[Category: Complex]] | + | [[Category: Wu B]] |
| - | [[Category: Gpcr]] | + | [[Category: Zhao Q]] |
| - | [[Category: Signaling protein]]
| + | |
| Structural highlights
6iiv is a 1 chain structure with sequence from Clostridium pasteurianum, Escherichia coli 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 3Å |
| Ligands: | , , , |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Disease
TA2R_HUMAN Bleeding diathesis due to thromboxane synthesis deficiency. Disease susceptibility is associated with variants affecting the gene represented in this entry.
Function
C562_ECOLX Electron-transport protein of unknown function.TA2R_HUMAN Receptor for thromboxane A2 (TXA2), a potent stimulator of platelet aggregation. The activity of this receptor is mediated by a G-protein that activates a phosphatidylinositol-calcium second messenger system. In the kidney, the binding of TXA2 to glomerular TP receptors causes intense vasoconstriction. Activates phospholipase C.[1] Activates adenylyl cyclase.[2] Inhibits adenylyl cyclase.[3] RUBR_CLOPA Rubredoxin is a small nonheme, iron protein lacking acid-labile sulfide. Its single Fe, chelated to 4 Cys, functions as an electron acceptor and may also stabilize the conformation of the molecule.
Publication Abstract from PubMed
Stimulated by thromboxane A2, an endogenous arachidonic acid metabolite, the thromboxane A2 receptor (TP) plays a pivotal role in cardiovascular homeostasis, and thus is considered as an important drug target for cardiovascular disease. Here, we report crystal structures of the human TP bound to two nonprostanoid antagonists, ramatroban and daltroban, at 2.5 A and 3.0 A resolution, respectively. The TP structures reveal a ligand-binding pocket capped by two layers of extracellular loops that are stabilized by two disulfide bonds, limiting ligand access from the extracellular milieu. These structures provide details of interactions between the receptor and antagonists, which help to integrate previous mutagenesis and SAR data. Molecular docking of prostanoid-like ligands, combined with mutagenesis, ligand-binding and functional assays, suggests a prostanoid binding mode that may also be adopted by other prostanoid receptors. These insights into TP deepen our understanding about ligand recognition and selectivity mechanisms of this physiologically important receptor.
Structural basis for ligand recognition of the human thromboxane A2 receptor.,Fan H, Chen S, Yuan X, Han S, Zhang H, Xia W, Xu Y, Zhao Q, Wu B Nat Chem Biol. 2019 Jan;15(1):27-33. doi: 10.1038/s41589-018-0170-9. Epub 2018, Dec 3. PMID:30510189[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Hirata T, Ushikubi F, Kakizuka A, Okuma M, Narumiya S. Two thromboxane A2 receptor isoforms in human platelets. Opposite coupling to adenylyl cyclase with different sensitivity to Arg60 to Leu mutation. J Clin Invest. 1996 Feb 15;97(4):949-56. PMID:8613548 doi:10.1172/JCI118518
- ↑ Hirata T, Ushikubi F, Kakizuka A, Okuma M, Narumiya S. Two thromboxane A2 receptor isoforms in human platelets. Opposite coupling to adenylyl cyclase with different sensitivity to Arg60 to Leu mutation. J Clin Invest. 1996 Feb 15;97(4):949-56. PMID:8613548 doi:10.1172/JCI118518
- ↑ Hirata T, Ushikubi F, Kakizuka A, Okuma M, Narumiya S. Two thromboxane A2 receptor isoforms in human platelets. Opposite coupling to adenylyl cyclase with different sensitivity to Arg60 to Leu mutation. J Clin Invest. 1996 Feb 15;97(4):949-56. PMID:8613548 doi:10.1172/JCI118518
- ↑ Fan H, Chen S, Yuan X, Han S, Zhang H, Xia W, Xu Y, Zhao Q, Wu B. Structural basis for ligand recognition of the human thromboxane A2 receptor. Nat Chem Biol. 2019 Jan;15(1):27-33. doi: 10.1038/s41589-018-0170-9. Epub 2018, Dec 3. PMID:30510189 doi:http://dx.doi.org/10.1038/s41589-018-0170-9
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