Structural basis for pharmacological modulation of the TRPC6 channel.

ELife
Yonghong BaiXin Huang

Abstract

Transient receptor potential canonical (TRPC) proteins form nonselective cation channels that play physiological roles in a wide variety of cells. Despite growing evidence supporting the therapeutic potential of TRPC6 inhibition in treating pathological cardiac and renal conditions, mechanistic understanding of TRPC6 function and modulation remains obscure. Here we report cryo-EM structures of TRPC6 in both antagonist-bound and agonist-bound states. The structures reveal two novel recognition sites for the small-molecule modulators corroborated by mutagenesis data. The antagonist binds to a cytoplasm-facing pocket formed by S1-S4 and the TRP helix, whereas the agonist wedges at the subunit interface between S6 and the pore helix. Conformational changes upon ligand binding illuminate a mechanistic rationale for understanding TRPC6 modulation. Furthermore, structural and mutagenesis analyses suggest several disease-related mutations enhance channel activity by disrupting interfacial interactions. Our results provide principles of drug action that may facilitate future design of small molecules to ameliorate TRPC6-mediated diseases.

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Citations

Sep 3, 2020·Cells·Xingjuan ChenAlexander G Obukhov
Oct 6, 2020·SLAS Discovery·Taiana Maia de OliveiraChris Phillips
Nov 26, 2020·ELife·Deivanayagabarathy VinayagamStefan Raunser
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Jul 14, 2021·Journal of Cell Science·Lixia Yue, Haoxing Xu

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Methods Mentioned

BETA
size exclusion chromatography
Assay
transfection

Software Mentioned

MotionCor2
CTFFIND4
Chimera
MolProbity
HOLE
PyMOL Molecular Graphics System
Pymol
Coot
Relion
ResMap

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