Structural basis for pharmacological modulation of the TRPC6 channel
- Amgen Inc, United States
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.
Data availability
The low pass filtered and amplitude modified 3D cryo-EM density maps for TRPC6 in complex with antagonist AM-1473 (accession code: EMD-20954) and agonist AM-0883 (accession code: EMD-20953) have been deposited in the electron microscopy data bank. Atomic coordinates for TRPC6 in complex with antagonist AM-1473 (accession code: 6UZA) and agonist AM-0883 (accession code: 6UZ8) have been deposited in the protein data bank.
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Cryo-EM structure of human TRPC6 in complex with antagonist AM-1473RCSB Protein Data Bank, 6UZA.
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Cryo-EM structure of human TRPC6 in complex with antagonist AM-1473Electron Microscopy Data Bank, EMD-20954.
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Cryo-EM structure of human TRPC6 in complex with agonist AM-0833RCSB Protein Data Bank, 6UZ8.
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Cryo-EM structure of human TRPC6 in complex with agonist AM-0833Electron Microscopy Data Bank, EMD-20953.
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Funding
No external funding was received for this work.
Copyright
© 2020, Bai et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Structural basis for pharmacological modulation of the TRPC6 channel
eLife 9:e53311.
https://doi.org/10.7554/eLife.53311
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