期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 290, 期 49, 页码 29127-29139出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M115.689000
关键词
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资金
- Department of Energy Office of Science by Argonne National Laboratory [DE-AC02-06CH11357]
- NCI [ACB-12002]
- NIGMS [AGM-12006]
Angiotensin II type 1 receptor (AT(1)R) is the primary blood pressure regulator. AT(1)R 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 toward cardiovascular etiologies. The structural basis for AT(1)R modulation by different peptide and non-peptide ligands has remained elusive. Here, we report the crystal structure of the human AT(1)R in complex with an inverse agonist olmesartan (Benicar (TM)), a highly potent anti-hypertensive drug. Olmesartan is anchored to the receptor primarily by the residues Tyr-35(1.39), Trp-84(2.60), and Arg-167(ECL2), 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 AT(1)R and different ARBs, including olmesartan derivatives with inverse agonist, neutral antagonist, or agonist activities. We further observed that the mutation N111(3.35)A in the putative sodium-binding site affects binding of the endogenous peptide agonist angiotensin II but not the beta-arrestin-biased peptide TRV120027.
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