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

  • Cell Res. 2018 Jul;28(7):746-755. doi: 10.1038/s41422-018-0038-2.
Qinglin Tang  1 ,  Wenjun Guo  1 ,  Li Zheng  2 ,  Jing-Xiang Wu  1  3 ,  Meng Liu  2 ,  Xindi Zhou  2 ,  Xiaolin Zhang  4 ,  Lei Chen  5  6
Affiliations
  • 1. State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, 100871, Beijing, China.
  • 2. Dizal Pharmaceutical Company, Jiangsu, China.
  • 3. Peking-Tsinghua Center for Life Sciences, Peking University, 100871, Beijing, China.
  • 4. Dizal Pharmaceutical Company, Jiangsu, China. [email protected].
  • 5. State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, 100871, Beijing, China. [email protected].
  • 6. Peking-Tsinghua Center for Life Sciences, Peking University, 100871, Beijing, China. [email protected].
PMID: 29700422 DOI: 10.1038/s41422-018-0038-2
Abstract

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.