Cryo-EM Structure of the TRPC1/5 Heteromer Enables Design of Antidepressant and Anxiolytic Drug with Reduced Side Effects.

Overview

Authors: Yixiang Chen¹, Tong Che^1,2, Xinyu Cheng¹, Xiaoqiang Yang³, Xiaojing Song⁴, Juncheng Li¹, Ying Fu¹, Wei Zhang¹, Sijia Lv¹, Tingting Yang¹, Qi Peng¹, Weiwei Nan³, Shuangyan Wan¹, Yaoguang Hua¹, Xiaoyun Wu³, Han Hu³, Yuting Zhang³, Yinzhen Liu³, Mingxing Yang³, Shuqi Zeng³

and 6 other authors

Ougen Liu⁵, Bo Yu¹, Jingjing Duan⁶, Jian Li², Bing Xiong⁷, Jin Zhang¹

ORCID iDs: Yixiang Chen, Tong Che, Jian Li, Bing Xiong, Jin Zhang

Institutions: Nanchang University (China); Gannan Medical University (China); Health Commission of Jiangxi Province (China); Second Affiliated Hospital of Nanchang University (China); Chinese Academy of Sciences (China)

Journal: Nature communications, volume 17, issue 1, article 6770

Dates: received 16 September 2025; accepted 30 April 2026; published online 23 May 2026

Type: Research article · Language: English

License: CC BY

Identifiers: DOI 10.1038/s41467-026-73409-1 · PMID 42177216 · PMCID PMC13385394 · OpenAlex W7162199886

Open access: gold, a free copy (OpenAlex)

Status: data only

Categories: histology / microscopy (modality), human (organism), mouse (organism), depression (population), cellular / molecular (subfield)

Methods: Statistics, Evoked potentials, fMRI & imaging

Keywords: Transient receptor potential channels, Cryoelectron microscopy

MeSH: Anti-Anxiety Agents*, Antidepressive Agents*, TRPC Cation Channels*, Animals, Binding Sites, Cryoelectron Microscopy, Drug Design, HEK293 Cells, Humans, Mice, Models, Molecular, Protein Multimerization (* major topic)

Topic: Ion Channels and Receptors (Sensory Systems, Neuroscience), according to OpenAlex

Funding: National Natural Science Foundation of China (National Science Foundation of China) (32271260); CAS “Light of West China” Program (xbzg-zdsys-202005), the Shenzhen Science and Technology Program (grant no. JCYJ20220818103017036 and KJZD20240903102205008) and the Jiangxi Province Natural Science Foundation (grant no. 20224ACB206046); Doctoral Startup Fund of Nanchang Medical College

Citations: not cited yet (Europe PMC); 56 references in the paper

Abstract

The TRPC1/5 heteromer exhibits electrophysiological and ligand-binding properties distinct from TRPC5 homomers, enabling tissue-specific cellular regulation. Here we present the cryo-EM structure of the TRPC1/5 heterotetramer at 2.8 Å resolution, revealing an asymmetric assembly of three TRPC5 subunits around one TRPC1 subunit. TRPC1 contributes a unique pore-loop configuration and specialized inter-subunit interfaces that sculpt an asymmetrical ion conduction pathway, altering gating and ion selectivity. The heteromer harbors a ligand-binding pocket at the TRPC1-TRPC5 interface absent in homomeric channels. Using this insight, we design JD03-02, a high-affinity antagonist preferentially targeting this pocket with >10,000-fold selectivity for TRPC1/5 over TRPC5 homomers. In mouse models, JD03-02 produces potent anxiolytic and antidepressant effects with reduced off-target activity. These findings elucidate the structural basis of TRPC1/5 function and can guide precision drug design targeting heteromeric ion channels in neuropsychiatric disorders.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

The paper links to its data, not to its authors' code: see the Data section.

The paper's code and data availability statement is in the Data section.

Tracing map

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Data

Datasets cited

ebi.ac.uk/emdb/emd-62060, at EMBL-EBI; found in “Data availability”
figshare:30171676, at figshare; found in “Data availability”

Data availability

The atomic coordinates and cryo-EM maps generated in this study have been deposited in the Protein Data Bank (PDB) under accession code 9K4I (https://doi.org/10.2210/pdb9K4I/pdb) and the Electron Microscopy Data Bank (EMDB) under accession code EMD-62060 (https://www.ebi.ac.uk/emdb/EMD-62060) The map and model identifiers are detailed in Supplementary Table 1. Additional source data have been deposited in Figshare (10.6084/m9.figshare.30171676). Source data for all figures are also provided with this paper as a Source Data file. Source data are provided with this paper.

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.

Version 1, 28 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 26 authors, 2 keywords, 12 MeSH terms, 3 funders, 55 references.

Cite

This paper

Chen, Y., Che, T., Cheng, X., Yang, X., Song, X., Li, J., Fu, Y., Zhang, W., Lv, S., Yang, T., Peng, Q., Nan, W., Wan, S., Hua, Y., Wu, X., Hu, H., Zhang, Y., Liu, Y., Yang, M., . . . Zhang, J. (2026). Cryo-EM Structure of the TRPC1/5 Heteromer Enables Design of Antidepressant and Anxiolytic Drug with Reduced Side Effects. Nature communications, 17(1), 6770. https://doi.org/10.1038/s41467-026-73409-1

BibTeX

@article{chen2026cryo, author = {Chen, Yixiang and Che, Tong and Cheng, Xinyu and Yang, Xiaoqiang and Song, Xiaojing and Li, Juncheng and Fu, Ying and Zhang, Wei and Lv, Sijia and Yang, Tingting and Peng, Qi and Nan, Weiwei and Wan, Shuangyan and Hua, Yaoguang and Wu, Xiaoyun and Hu, Han and Zhang, Yuting and Liu, Yinzhen and Yang, Mingxing and Zeng, Shuqi and Liu, Ougen and Yu, Bo and Duan, Jingjing and Li, Jian and Xiong, Bing and Zhang, Jin}, title = {{Cryo-EM Structure of the TRPC1/5 Heteromer Enables Design of Antidepressant and Anxiolytic Drug with Reduced Side Effects}}, journal = {Nature communications}, year = {2026}, month = may, volume = {17}, number = {1}, pages = {6770}, publisher = {Nature Publishing Group}, issn = {2041-1723}, doi = {10.1038/s41467-026-73409-1}, url = {https://doi.org/10.1038/s41467-026-73409-1}, pmid = {42177216}, pmcid = {PMC13385394} }

RIS

TY - JOUR AU - Chen, Yixiang AU - Che, Tong AU - Cheng, Xinyu AU - Yang, Xiaoqiang AU - Song, Xiaojing AU - Li, Juncheng AU - Fu, Ying AU - Zhang, Wei AU - Lv, Sijia AU - Yang, Tingting AU - Peng, Qi AU - Nan, Weiwei AU - Wan, Shuangyan AU - Hua, Yaoguang AU - Wu, Xiaoyun AU - Hu, Han AU - Zhang, Yuting AU - Liu, Yinzhen AU - Yang, Mingxing AU - Zeng, Shuqi AU - Liu, Ougen AU - Yu, Bo AU - Duan, Jingjing AU - Li, Jian AU - Xiong, Bing AU - Zhang, Jin TI - Cryo-EM Structure of the TRPC1/5 Heteromer Enables Design of Antidepressant and Anxiolytic Drug with Reduced Side Effects T2 - Nature communications J2 - Nat Commun PY - 2026 DA - 2026/05/23 VL - 17 IS - 1 SP - 6770 SN - 2041-1723 PB - Nature Publishing Group DO - 10.1038/s41467-026-73409-1 UR - https://doi.org/10.1038/s41467-026-73409-1 LA - en ER -

CSL-JSON

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