Structural basis of TRPC4 regulation by calmodulin and pharmacological agents
- Max Planck Institute of Molecular Physiology, Germany
- Julius-Maximilians-Universität Würzburg, Germany
- Max Planck Institute for Molecular Physiology, Germany
- Goldfinch Bio Inc, United States
Abstract
Canonical transient receptor potential channels (TRPC) are involved in receptor-operated and/or store-operated Ca2+ signaling. Inhibition of TRPCs by small molecules was shown to be promising in treating renal diseases. In cells, the channels are regulated by calmodulin. Molecular details of both calmodulin and drug binding have remained elusive so far. Here we report structures of TRPC4 in complex with three pyridazinone-based inhibitors and calmodulin. The structures reveal that all the inhibitors bind to the same cavity of the voltage-sensing-like domain and allow us to describe how structural changes from the ligand binding site can be transmitted to the central ion-conducting pore of TRPC4. Calmodulin binds to the rib helix of TRPC4, which results in the ordering of a previously disordered region, fixing the channel in its closed conformation. This represents a novel calmodulin-induced regulatory mechanism of canonical TRP channels.
Data availability
The atomic coordinates and cryo-EM maps for TRPC4DR in complex with inhibitors, calmodulin and for TRPC4DR in LMNG are available at the Protein Data Bank (PDB) and Electron Microscopy Data Bank (EMDB) databases, under the accession numbers PBD 7B0S and EMD-11970 (TRPC4-GFB8438), PBD 7B16 and EMD-11979 (TRPC4-GFB9289); PBD 7B05 and EMD-11957 (TRPC4-GFB8749); PBD 7B1G and EMD-11985 (TRPC4-Calmodulin) and PBD 7B0J and EMD-11968 (TRPC4-apo in LMNG).
Article and author information
Author details
Funding
Max-Planck-Gesellschaft
- Stefan Raunser
Deutsche Forschungsgemeinschaft (TR240)
- Georg Nagel
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Leon D Islas, Universidad Nacional Autónoma de México, Mexico
Publication history
- Received: July 1, 2020
- Accepted: November 23, 2020
- Accepted Manuscript published: November 25, 2020 (version 1)
- Version of Record published: December 14, 2020 (version 2)
Copyright
© 2020, Vinayagam 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 of TRPC4 regulation by calmodulin and pharmacological agents
eLife 9:e60603.
https://doi.org/10.7554/eLife.60603
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