|
 |
|
|
|
EMBO reports 9, 2, 179–186 (2008)
doi:10.1038/sj.embor.7401157
AOP Published online: 18 January 2008
Conformational switch of angiotensin II type 1 receptor underlying mechanical stress-induced activation
Noritaka Yasuda1*, Shin-ichiro Miura2*, Hiroshi Akazawa1, 3*, Toshimasa Tanaka4, Yingjie Qin1, Yoshihiro Kiya2, Satoshi Imaizumi2, Masahiro Fujino2, Kaoru Ito1, Yunzeng Zou5, Shigetomo Fukuhara6, Satoshi Kunimoto6, Koichi Fukuzaki7, Toshiaki Sato7, Junbo Ge5, Naoki Mochizuki6, Haruaki Nakaya7, Keijiro Saku2 & Issei Komuro1
|
|
|
|
1 Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
2 Department of Cardiology, Fukuoka University School of Medicine, 7-45-1, Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan
3 Division of Cardiovascular Pathophysiology, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
4 Pharmaceutical Research Division, Discovery Research Center, Takeda Pharmaceutical Company Limited, 2–17–85 Juso-Honmachi, Yodogawa-ku, Osaka, 532-8686, Japan
5 Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, 180 Feng Lin Road, Shanghai 200032, China
6 Department of Structural Analysis, National Cardiovascular Center Research Institute, 5-7-1 Fujishirodai, Suita, Osaka 565-8565, Japan
7 Department of Pharmacology, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
To whom correspondence should be addressed
Issei Komuro Tel: +81 43 226 2097; Fax: +81 43 226 2557; E-mail: komuro-tky@umin.ac.jp
* These authors contributed equally to this work
Received 20 June 2007; Accepted 28 November 2007; Published online 18 January 2008.
|
|
|
|
Abstract
The angiotensin II type 1 (AT1) 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 AT1 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 AT1 receptor stabilizes the receptor in the inactive conformation, preventing its shift to the active conformation. Our results show that the AT1 receptor undergoes a conformational switch that couples mechanical stress-induced activation and inverse agonist-induced inactivation.
|
 |
|
Top of page MORE ARTICLES LIKE THIS These links to content published by NPG are automatically generated | |
|
top  |
|
|
|
