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Structural basis for human TRPC5 channel inhibition by two distinct inhibitors

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 pr...

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Autores principales: Song, Kangcheng, Wei, Miao, Guo, Wenjun, Quan, Li, Kang, Yunlu, Wu, Jing-Xiang, Chen, Lei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987348/
https://www.ncbi.nlm.nih.gov/pubmed/33683200
http://dx.doi.org/10.7554/eLife.63429
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author Song, Kangcheng
Wei, Miao
Guo, Wenjun
Quan, Li
Kang, Yunlu
Wu, Jing-Xiang
Chen, Lei
author_facet Song, Kangcheng
Wei, Miao
Guo, Wenjun
Quan, Li
Kang, Yunlu
Wu, Jing-Xiang
Chen, Lei
author_sort Song, Kangcheng
collection PubMed
description 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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spelling pubmed-79873482021-03-24 Structural basis for human TRPC5 channel inhibition by two distinct inhibitors Song, Kangcheng Wei, Miao Guo, Wenjun Quan, Li Kang, Yunlu Wu, Jing-Xiang Chen, Lei eLife Structural Biology and Molecular Biophysics 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. eLife Sciences Publications, Ltd 2021-03-08 /pmc/articles/PMC7987348/ /pubmed/33683200 http://dx.doi.org/10.7554/eLife.63429 Text en © 2021, Song et al http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Structural Biology and Molecular Biophysics
Song, Kangcheng
Wei, Miao
Guo, Wenjun
Quan, Li
Kang, Yunlu
Wu, Jing-Xiang
Chen, Lei
Structural basis for human TRPC5 channel inhibition by two distinct inhibitors
title Structural basis for human TRPC5 channel inhibition by two distinct inhibitors
title_full Structural basis for human TRPC5 channel inhibition by two distinct inhibitors
title_fullStr Structural basis for human TRPC5 channel inhibition by two distinct inhibitors
title_full_unstemmed Structural basis for human TRPC5 channel inhibition by two distinct inhibitors
title_short Structural basis for human TRPC5 channel inhibition by two distinct inhibitors
title_sort structural basis for human trpc5 channel inhibition by two distinct inhibitors
topic Structural Biology and Molecular Biophysics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987348/
https://www.ncbi.nlm.nih.gov/pubmed/33683200
http://dx.doi.org/10.7554/eLife.63429
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