Journal
CELL RESEARCH
Volume 28, Issue 7, Pages 746-755Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41422-018-0038-2
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Funding
- National Center for Protein Science (Shanghai)
- Ministry of Science and Technology of China (National Key R&D Program of China) [2016YFA0502004]
- National Natural Science Foundation of China [31622021, 31521062]
- Young Thousand Talents Program of China
- China Postdoctoral Science Foundation [2016M600856, 2017T100014]
- postdoctoral foundation of the Peking-Tsinghua Center for Life Sciences, Peking University
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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 angstrom resolution. We also present the structure of human TRPC3 at 4.4 angstrom 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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