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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^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.