TRPC5公司
化学
生物物理学
蛋白质亚单位
抑制性突触后电位
细胞生物学
结合位点
离子通道
TRPC1型
生物化学
生物
受体
神经科学
基因
作者
Kangcheng Song,Miao Wei,Wenjun Guo,Li Quan,Yunlu Kang,Jing-Xiang Wu,Lei Chen
出处
期刊:eLife
[eLife Sciences Publications Ltd]
日期:2021-03-08
卷期号:10
被引量:71
摘要
TRPC5 channel is a nonselective cation channel that participates in diverse physiological processes. TRPC5 inhibitors show promise in the treatment of anxiety disorder, depression, and kidney disease. However, the binding sites and inhibitory mechanism of TRPC5 inhibitors remain elusive. Here, we present the cryo-EM structures of human TRPC5 in complex with two distinct inhibitors, namely clemizole and HC-070, to the resolution of 2.7 Å. The structures reveal that clemizole binds inside the voltage sensor-like domain of each subunit. In contrast, HC-070 is wedged between adjacent subunits and replaces the glycerol group of a putative diacylglycerol molecule near the extracellular side. Moreover, we found mutations in the inhibitor binding pockets altered the potency of inhibitors. These structures suggest that both clemizole and HC-070 exert the inhibitory functions by stabilizing the ion channel in a nonconductive closed state. These results pave the way for further design and optimization of inhibitors targeting human TRPC5.
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