Conformational switch of angiotensin II type 1 receptor underlying mechanical stress-induced activation
Conformational switch of angiotensin II type 1 receptor underlying mechanical stress-induced activation
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DOI：
10.1038/sj.embor.7401157
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发表时间：
2008-02-01
期刊：
影响因子：
7.7
通讯作者：
Komuro, Issei
中科院分区：
文献类型：
--
作者：
Yasuda, Noritaka;Miura, Shin-ichiro;Komuro, Issei
血管紧张素II 1型受体(AT(1))是一种G蛋白偶联受体，在负荷性心肌肥厚的发生发展中起重要作用。在这里，我们展示了细胞拉伸导致AT1受体的激活，该受体经历了逆时针旋转和跨膜(TM)7进入配体结合口袋的移位。作为反向激动剂，坎地沙坦通过将坎地沙坦的羧基与受体的特定残基结合来抑制拉伸诱导的TM7的螺旋运动。一个分子模型认为坎地沙坦与AT(1)受体的紧密结合稳定了受体的非活性构象，防止了它向活性构象的转变。我们的结果表明，AT(1)受体经历了机械应激诱导的激活和反向激动剂诱导的失活的构象转换。
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 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 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.