Cryo-EM Structure of the TRPC1/5 Heteromer Enables Design of Antidepressant and Anxiolytic Drug with Reduced Side Effects
Abstract
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.
Article Details
Authors (26)
Yixiang Chen
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.
Tong Che
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.
Xinyu Cheng
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.
Xiaoqiang Yang
Zhejiang Key Laboratory of Medical Epigenetics, Department of Immunology and Pathogen Biology, School of Basic Medical Sciences, Hangzhou Normal University
Xiaojing Song
Juncheng Li
The RNA Institute
Ying Fu
Wei Zhang
Sijia Lv
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.
Tingting Yang
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.
Qi Peng
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.
Weiwei Nan
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.
Shuangyan Wan
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.
Yaoguang Hua
Xiaoyun Wu
Han Hu
Yuting Zhang
Shenzhen Crystalo Biopharmaceutical Co., Ltd., Shenzhen, Guangdong, China.
Yinzhen Liu
Mingxing Yang
Shuqi Zeng
Ougen Liu
Bo Yu
Jingjing Duan
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, China.
Jian Li
Bing Xiong
Jin Zhang