4zud | pdb_00004zud

Crystal Structure of Human Angiotensin Receptor in Complex with Inverse Agonist Olmesartan at 2.8A resolution.

spinqualitylabelsall models 4zud, resolution 2.80Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4zud is a 1 chain structure with sequence from Escherichia coli and Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: OLM Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease AGTR1_HUMAN NON RARE IN EUROPE: Essential hypertension;Renal tubular dysgenesis of genetic origin. The disease is caused by mutations affecting the gene represented in this entry. Function C562_ECOLX Electron-transport protein of unknown function.AGTR1_HUMAN Receptor for angiotensin II. Mediates its action by association with G proteins that activate a phosphatidylinositol-calcium second messenger system. Publication Abstract from PubMed Angiotensin II type 1 receptor (AT1R) is the primary blood pressure regulator. AT1R blockers (ARBs) have been widely used in clinical settings as anti-hypertensive drugs, and share a similar chemical scaffold, although even minor variations can lead to distinct therapeutic efficacies towards cardiovascular etiologies. The structural basis for AT1R modulation by different peptide and non-peptide ligands has remained elusive. Here we report the crystal structure of the human AT1R in complex with an inverse agonist olmesartan (BenicarTM), a highly potent anti-hypertensive drug. Olmesartan is anchored to the receptor primarily by the residues Tyr351.39, Trp842.60, and Arg167ECL2, similar to the antagonist ZD7155, corroborating a common binding mode of different ARBs. Using docking simulations and site-directed mutagenesis we identified specific interactions between AT1R and different ARBs, including olmesartan derivatives with inverse agonist, neutral antagonist or agonist activities. We further observed that the mutation Asn1113.35Ala in the putative sodium-binding site affects binding of the endogenous peptide agonist Angiotensin II, but not the beta-arrestin-biased peptide TRV120027. Structural Basis for Ligand Recognition and Functional Selectivity at Angiotensin Receptor.,Zhang H, Unal H, Desnoyer R, Han GW, Patel N, Katritch V, Karnik SS, Cherezov V, Stevens RC J Biol Chem. 2015 Sep 29. pii: jbc.M115.689000. PMID:26420482 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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