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 huma...

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Vydáno v:Cell research Ročník 28; číslo 7; s. 746 - 755
Hlavní autoři: Tang, Qinglin, Guo, Wenjun, Zheng, Li, Wu, Jing-Xiang, Liu, Meng, Zhou, Xindi, Zhang, Xiaolin, Chen, Lei
Médium: Journal Article
Jazyk:angličtina
Vydáno: London Nature Publishing Group UK 01.07.2018
Nature Publishing Group
Témata:
101/28
631/535/1258/1259
631/80/313/2380
9/74
Affinity
Ankyrins
Biomedical and Life Sciences
Cell Biology
Channel opening
Diglycerides
Electron microscopy
Inhibitors
Ion channels
Ions
Life Sciences
Molecular chains
Transient receptor potential proteins
ISSN:1001-0602, 1748-7838, 1748-7838
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Shrnutí: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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ISSN:1001-0602
1748-7838
1748-7838
DOI:10.1038/s41422-018-0038-2