Cryo-EM Structure of the TRPC1/5 Heteromer Enables Design of Antidepressant and Anxiolytic Drug with Reduced Side Effects
- Yixiang Chen
- Tong Che
- Xinyu Cheng
- Xiaoqiang Yang
- Xiaojing Song
- Juncheng Li
- Ying Fu
- Wei Zhang
- Sijia Lv
- Tingting Yang
- Qi Peng
- Weiwei Nan
- Shuangyan Wan
- Yaoguang Hua
- Xiaoyun Wu
- Han Hu
- Yuting Zhang
- Yinzhen Liu
- Mingxing Yang
- Shuqi Zeng
- Ougen Liu
- Bo Yu
- Jingjing Duan
- Jian Li
- Bing Xiong
- Jin Zhang
2026-05-23
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.