6iiv

Crystal structure of the human thromboxane A2 receptor bound to daltroban

spinqualitylabelsall models 6iiv, resolution 3.00Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D 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: A90, CLR, GOL, ZN 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. Activates adenylyl cyclase. Inhibits adenylyl cyclase. 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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