Structural basis for human TRPC5 channel inhibition by two distinct inhibitors

Abstract

TRPC5 channel is a non-selective cation channel that participates 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 DAG 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 non-conductive closed state. These results pave the way for further design and optimization of inhibitors targeting human TRPC5.

Data availability

The density maps of hTRPC5 have been deposited to the Electron Microscopy Data Bank (EMDB) under the accession number: EMD-30987 for apo hTRPC5, EMD-30575 for CMZ-bound hTRPC5 and EMD-30576 for HC-070-bound hTRPC5. Coordinates of atomic model have been deposited in the Protein Data Bank (PDB) under the accession number: 7E4T for apo hTRPC5, 7D4P for CMZ-bound hTRPC5 and 7D4Q for HC-070-bound hTRPC5.

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Kangcheng Song

    Institute of Molecular Medicine, Peking University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  2. Miao Wei

    Institute of Molecular Medicine, Peking University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  3. Wenjun Guo

    Institute of Molecular Medicine, Peking University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  4. Li Quan

    Institute of Molecular Medicine, Peking University, Beijjing, China
    Competing interests
    The authors declare that no competing interests exist.
  5. Yunlu Kang

    Institute of Molecular Medicine, Peking University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  6. Jing-Xiang Wu

    Institute of Molecular Medicine, Peking University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9851-0065
  7. Lei Chen

    Institute of Molecular Medicine, Peking University, Beijjing, China
    For correspondence
    chenlei2016@pku.edu.cn
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7619-8311

Funding

National Key Research and Development Program of China (2016YFA0502004)

  • Lei Chen

National Natural Science Foundation of China (91957201,31870833,31821091)

  • Lei Chen

National Natural Science Foundation of China (31900859)

  • Jing-Xiang Wu

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Randy B Stockbridge, University of Michigan, United States

Publication history

  1. Received: September 24, 2020
  2. Accepted: March 5, 2021
  3. Accepted Manuscript published: March 8, 2021 (version 1)
  4. Version of Record published: March 22, 2021 (version 2)

Copyright

© 2021, Song et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Kangcheng Song
  2. Miao Wei
  3. Wenjun Guo
  4. Li Quan
  5. Yunlu Kang
  6. Jing-Xiang Wu
  7. Lei Chen
(2021)
Structural basis for human TRPC5 channel inhibition by two distinct inhibitors
eLife 10:e63429.
https://doi.org/10.7554/eLife.63429

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