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Structure of the receptor-activated human TRPC6 and TRPC3 ion channels


TRPC6 and TRPC3 are receptor-activated nonselective cation channels that belong to the family of canonical transient receptor potential (TRPC) channels. They are activated by diacylglycerol, a lipid second messenger. TRPC6 and TRPC3 are involved in many physiological processes and implicated in human genetic diseases. Here we present the structure of human TRPC6 homotetramer in complex with a newly identified high-affinity inhibitor BTDM solved by single-particle cryo-electron microscopy to 3.8 Å resolution. We also present the structure of human TRPC3 at 4.4 Å resolution. These structures show two-layer architectures in which the bell-shaped cytosolic layer holds the transmembrane layer. Extensive inter-subunit interactions of cytosolic domains, including the N-terminal ankyrin repeats and the C-terminal coiled-coil, contribute to the tetramer assembly. The high-affinity inhibitor BTDM wedges between the S5-S6 pore domain and voltage sensor-like domain to inhibit channel opening. Our structures uncover the molecular architecture of TRPC channels and provide a structural basis for understanding the mechanism of these channels.

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We thank all of Chen Laboratory members for their kind help. Cryo-EM data collection was supported by the National Center for Protein Science (Shanghai) with assistance of Liangliang Kong and Zhenglin Fu, Electron Microscopy Laboratory and Cryo-EM platform of Peking University with assistance of Xuemei Li and Daqi Yu, and Center for Biological Imaging, Institute of Biophysics, Chinese Academy of Science with assistance of Zhenxi Guo. Part of structural computation was also performed on the Computing Platform of the Center for Life Science and High-performance Computing Platform of Peking University. The work is supported by grants from the Ministry of Science and Technology of China (National Key R&D Program of China, 2016YFA0502004 to L.C.), National Natural Science Foundation of China (31622021 and 31521062 to L.C.), Young Thousand Talents Program of China to L.C. and the China Postdoctoral Science Foundation (2016M600856 and 2017T100014 to J.-X.W.). J.-X.W. is supported by the postdoctoral foundation of the Peking-Tsinghua Center for Life Sciences, Peking University.

Author information

X. Zhang and L.C. initiated the project. Q.T., W.G., L.Z., M.L., X. Zhou, X. Zhang, and L.C. designed the experiments. Q.T., W.G., J.-X.W., and L.C. prepared the EM sample, collected the EM data, performed image processing, and built the model. Q.T. and W.G. generated mutants. L.Z., M.L., X. Zhou, and X. Zhang provided BTDM and performed electrophysiology recording and FLIPR assay. Q.T., W.G., J.-X.W., and L.C. wrote the manuscript draft. All authors contributed to manuscript preparation.

Competing interests

L.Z., M.L., X. Zhou and X. Zhang are employees of Dizal Pharmaceutical Company. The other authors declare no competing interests.

Correspondence to Xiaolin Zhang or Lei Chen.

Electronic supplementary material

  1. Supplementary information, Table S1

  2. Supplementary information, Table S2

  3. Supplementary information, Figure S1

  4. Supplementary information, Figure S2

  5. Supplementary information, Figure S3

  6. Supplementary information, Figure S4

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