2. Academic Validation
  3. Structural mechanism of the agonist binding on human TRPC3 channel

Structural mechanism of the agonist binding on human TRPC3 channel

  • Nat Commun. 2025 Oct 22;16(1):9343. doi: 10.1038/s41467-025-64435-6.
Yikun Chen # 1 2,  Jiahe Zang # 1,  Wenjun Guo # 1 2 3,  Jiaxuan Xu 1,  Miao Wei 1,  Li Quan 1,  Min Zhu 4,  Xiaole Zhao 5,  Hailin Peng 5,  Yakun Wan 4,  Lei Chen 6 7 8 9
Affiliations

Affiliations

  • 1 State Key Laboratory of Membrane Biology, College of Future Technology, Institute of Molecular Medicine, Peking University, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Beijing, China.
  • 2 Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China.
  • 3 Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China.
  • 4 Shanghai Novamab Biopharmaceuticals Co, Ltd, Shanghai, China.
  • 5 Center for Nanochemistry, Beijing Science and Engineering Center for Nanocarbons, Beijing National Laboratory for Molecular Sciences, College of Chemistry and Molecular Engineering, Peking University, Beijing, China.
  • 6 State Key Laboratory of Membrane Biology, College of Future Technology, Institute of Molecular Medicine, Peking University, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Beijing, China. [email protected].
  • 7 Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China. [email protected].
  • 8 Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China. [email protected].
  • 9 National Biomedical Imaging Center, Peking University, Beijing, China. [email protected].
  • # Contributed equally.
PMID: 41125595 DOI: 10.1038/s41467-025-64435-6
Abstract

TRPC3/6/7 channels are cation channels that are directly activated by the second messenger diacylglycerol (DAG). These channels play crucial physiological roles and are implicated in various disease conditions; however, the binding mechanism of DAG to these channels remains incompletely understood. In this study, we present the structures of human TRPC3 in complex with DAG or synthetic activators, 4n and GSK1702934A. The structural analysis reveals that DAG binds at the L2 site, located near the pore on the extracellular side of TRPC3. Functional assays confirmed that the L2 site serves as the activating site for DAG. Notably, both 4n and GSK1702934A competitively bind to the same site, facilitating channel activation. Moreover, based on the pharmacophore identified from the DAG-bound structure, we found that monoacylglycerols (MAGs) are endogenous activators of TRPC3/6/7 channels, providing new insights into their regulatory mechanisms.

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