title: Conformational switch of angiotensin II type 1 receptor underlying mechanical stress-induced activation.
abstract: The angiotensin II type 1 (AT(1)) receptor is a G protein-coupled receptor that has a crucial role in the development of load-induced cardiac hypertrophy. Here, we show that cell stretch leads to activation of the AT(1) receptor, which undergoes an anticlockwise rotation and a shift of transmembrane (TM) 7 into the ligand-binding pocket. As an inverse agonist, candesartan suppressed the stretch-induced helical movement of TM7 through the bindings of the carboxyl group of candesartan to the specific residues of the receptor. A molecular model proposes that the tight binding of candesartan to the AT(1) receptor stabilizes the receptor in the inactive conformation, preventing its shift to the active conformation. Our results show that the AT(1) receptor undergoes a conformational switch that couples mechanical stress-induced activation and inverse agonist-induced inactivation.
authors.affiliation: Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
authors.forename: Noritaka
authors.initials: N
authors.lastname: Yasuda
authors.forename: Shin-ichiro
authors.initials: S
authors.lastname: Miura
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Akazawa
authors.forename: Toshimasa
authors.initials: T
authors.lastname: Tanaka
authors.forename: Yingjie
authors.initials: Y
authors.lastname: Qin
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kiya
authors.forename: Satoshi
authors.initials: S
authors.lastname: Imaizumi
authors.forename: Masahiro
authors.initials: M
authors.lastname: Fujino
authors.forename: Kaoru
authors.initials: K
authors.lastname: Ito
authors.forename: Yunzeng
authors.initials: Y
authors.lastname: Zou
authors.forename: Shigetomo
authors.initials: S
authors.lastname: Fukuhara
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kunimoto
authors.forename: Koichi
authors.initials: K
authors.lastname: Fukuzaki
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Sato
authors.forename: Junbo
authors.initials: J
authors.lastname: Ge
authors.forename: Naoki
authors.initials: N
authors.lastname: Mochizuki
authors.forename: Haruaki
authors.initials: H
authors.lastname: Nakaya
authors.forename: Keijiro
authors.initials: K
authors.lastname: Saku
authors.forename: Issei
authors.initials: I
authors.lastname: Komuro
mesh_terms: D001562:Benzimidazoles / Q000737:chemistry / Q000494:pharmacology; D001713:Biphenyl Compounds; D002460:Cell Line; D006801:Humans; D008958:Models, Molecular; D017433:Protein Structure, Secondary; D044140:Receptor, Angiotensin, Type 1 / Q000819:agonists / Q000737:chemistry* / Q000378:metabolism*; D012399:Rotation; D013314:Stress, Mechanical; D013777:Tetrazoles / Q000737:chemistry / Q000494:pharmacology
chemical_list: D001562:Benzimidazoles; D001713:Biphenyl Compounds; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; C081643:candesartan