Conformational switch of angiotensin II type 1 receptor underlying mechanical stress-induced activation.
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.
Yasuda
Noritaka
N
Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
Miura
Shin-ichiro
S
Akazawa
Hiroshi
H
Tanaka
Toshimasa
T
Qin
Yingjie
Y
Kiya
Yoshihiro
Y
Imaizumi
Satoshi
S
Fujino
Masahiro
M
Ito
Kaoru
K
Zou
Yunzeng
Y
Fukuhara
Shigetomo
S
Kunimoto
Satoshi
S
Fukuzaki
Koichi
K
Sato
Toshiaki
T
Ge
Junbo
J
Mochizuki
Naoki
N
Nakaya
Haruaki
H
Saku
Keijiro
K
Komuro
Issei
I
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
D001562:Benzimidazoles; D001713:Biphenyl Compounds; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; C081643:candesartan