6iiu

From Proteopedia

(Difference between revisions)

Current revision

Crystal structure of the human thromboxane A2 receptor bound to ramatroban

Structural highlights

6iiu 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 2.5Å
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

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6iiu"

@@ Line 5: / Line 5: @@
 <table><tr><td colspan='2'>[[6iiu]] 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=6IIU OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6IIU FirstGlance]. <br>
 </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.5&#8491;</td></tr>
-<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A8X:3-[(3R)-3-[(4-fluorophenyl)sulfonylamino]-1,2,3,4-tetrahydrocarbazol-9-yl]propanoic+acid'>A8X</scene>, <scene name='pdbligand=CLR:CHOLESTEROL'>CLR</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=OLC:(2R)-2,3-DIHYDROXYPROPYL+(9Z)-OCTADEC-9-ENOATE'>OLC</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A8X:3-[(3~{R})-3-[(4-fluorophenyl)sulfonylamino]-1,2,3,4-tetrahydrocarbazol-9-yl]propanoic+acid'>A8X</scene>, <scene name='pdbligand=CLR:CHOLESTEROL'>CLR</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=OLC:(2R)-2,3-DIHYDROXYPROPYL+(9Z)-OCTADEC-9-ENOATE'>OLC</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'>[https://proteopedia.org/fgij/fg.htm?mol=6iiu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6iiu OCA], [https://pdbe.org/6iiu PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6iiu RCSB], [https://www.ebi.ac.uk/pdbsum/6iiu PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6iiu ProSAT]</span></td></tr>
 </table>

6iiu

From Proteopedia

Current revision

Crystal structure of the human thromboxane A2 receptor bound to ramatroban

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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