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bioRxiv · 10.1101/282814

Structure of the receptor-activated human TRPC6 ion channel

Tang, Q.·Guo, W.·Zheng, L.·Wu, J.-X.·Liu, M.·Zhou, X.·Zhang, X.·Chen, L.
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Abstract

TRPC6 is a receptor-activated nonselective cation channel that belongs to the family of canonical transient receptor potential (TRPC) channels. It is activated by diacylglycerol, a lipid second messenger. TRPC6 is 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 [A] resolution. The structure shows a two-layer architecture, in which the bell-shaped cytosolic layer holds the transmembrane layer. Extensive inter-subunit interactions of cytosolic domain, including N terminal ankyrin repeats and C terminal coiled-coil, contribute to the tetramer assembly. The high affinity inhibitor BTDM wedges between S5-S6 pore domain and voltage sensor-like domain to inhibit channel opening. Our structure uncovers the molecular architecture of TRPC channels and provides a structural basis for understanding the mechanism of these channels.

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Tang, Q., Guo, W., Zheng, L., Wu, J.-X., Liu, M., Zhou, X., Zhang, X., Chen, L.. 2018-03-15. Structure of the receptor-activated human TRPC6 ion channel. https://doi.org/10.1101/282814

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