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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...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2021
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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. |
format | Online Article Text |
id | pubmed-7987348 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
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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