Cryo-EM Structure of the TRPC1/5 Heteromer Enables Design of Antidepressant and Anxiolytic Drug with Reduced Side Effects PMID: 42177216

Target-related Cytokines

2026-09-23

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

Nat Commun. 2026 May 23. doi: 10.1038/s41467-026-73409-1.

Yixiang Chen ^# ¹ , Tong Che ^# ¹ ² , Xinyu Cheng ^# ¹ , Xiaoqiang Yang ^# ³ , Xiaojing Song ⁴ , Juncheng Li ¹ , Ying Fu ¹ , Wei Zhang ¹ , Sijia Lv ¹ , Tingting Yang ¹ , Qi Peng ¹ , Weiwei Nan ³ , Shuangyan Wan ¹ , Yaoguang Hua ¹ , Xiaoyun Wu ³ , Han Hu ³ , Yuting Zhang ³ , Yinzhen Liu ³ , Mingxing Yang ³ , Shuqi Zeng ³ , Ougen Liu ⁵ , Bo Yu ¹ , Jingjing Duan ⁶ , Jian Li ⁷ , Bing Xiong ⁸ , Jin Zhang ⁹

Affiliations

1. The MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors, School of Basic Medical Sciences; The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China.
2. Jiangxi Province Key Laboratory of Pharmacology of Traditional Chinese Medicine, School of Pharmacy, First Affiliated Hospital, Gannan Medical University, Ganzhou, Jiangxi, 341000, China.
3. Shenzhen Crystalo Biopharmaceutical Co., Ltd, Shenzhen, Guangdong, 518118, China.
4. Key Laboratory of Infection and Immunity, Health Commission of Jiangxi Province & School of Basic Medicine, Nanchang Medical College, Nanchang, 330052, P. R. China.
5. Department of Dermatology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China.
6. Sphingolipid Metabolism and Aging, Human Aging Research Institute (HARI) and School of Life Science, Nanchang University, Jiangxi Key Laboratory of Aging and Disease, Nanchang, Jiangxi, 330031, China. [email protected].
7. Jiangxi Province Key Laboratory of Pharmacology of Traditional Chinese Medicine, School of Pharmacy, First Affiliated Hospital, Gannan Medical University, Ganzhou, Jiangxi, 341000, China. [email protected].
8. State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, P. R. China. [email protected].
9. The MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors, School of Basic Medical Sciences; The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China. [email protected].
# Contributed equally.

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.