National Natural Science Foundation of China (NSFC)
31622021
China
National Science Foundation (NSF, China)
91857000
China
National Science Foundation (NSF, China)
31821091
China
National Natural Science Foundation of China (NSFC)
China
Citation
Journal: Elife / Year: 2021 Title: Structural basis for human TRPC5 channel inhibition by two distinct inhibitors. Authors: Kangcheng Song / Miao Wei / Wenjun Guo / Li Quan / Yunlu Kang / Jing-Xiang Wu / Lei Chen / Abstract: 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. ...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.
History
Deposition
Sep 24, 2020
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Header (metadata) release
Mar 31, 2021
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Map release
Mar 31, 2021
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Update
Oct 13, 2021
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Current status
Oct 13, 2021
Processing site: PDBj / Status: Released
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