PUBLICATION
Structural basis of TRPC4 regulation by calmodulin and pharmacological agents
- Authors
- Vinayagam, D., Quentin, D., Yu-Strzelczyk, J., Sitsel, O., Merino, F., Stabrin, M., Hofnagel, O., Yu, M., Ledeboer, M.W., Nagel, G., Malojcic, G., Raunser, S.
- ID
- ZDB-PUB-210317-20
- Date
- 2020
- Source
- eLIFE 9: (Journal)
- Registered Authors
- Keywords
- calmodulin, canonical transient receptor potential channel, cryo-EM, ion channel, modulation, molecular biophysics, none, regulation, structural biology
- MeSH Terms
-
- Animals
- Binding Sites
- Calmodulin/chemistry
- Calmodulin/genetics
- Calmodulin/metabolism*
- HEK293 Cells
- Humans
- Ligands
- Membrane Potentials
- Membrane Transport Modulators/chemistry
- Membrane Transport Modulators/metabolism
- Membrane Transport Modulators/pharmacology*
- Models, Molecular
- Protein Binding
- Protein Conformation
- Pyridazines/chemistry
- Pyridazines/metabolism
- Pyridazines/pharmacology*
- Sf9 Cells
- Structure-Activity Relationship
- TRPC Cation Channels/chemistry
- TRPC Cation Channels/drug effects*
- TRPC Cation Channels/genetics
- TRPC Cation Channels/metabolism
- Xenopus
- Zebrafish Proteins/chemistry
- Zebrafish Proteins/drug effects*
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism
- PubMed
- 33236980 Full text @ Elife
Citation
Vinayagam, D., Quentin, D., Yu-Strzelczyk, J., Sitsel, O., Merino, F., Stabrin, M., Hofnagel, O., Yu, M., Ledeboer, M.W., Nagel, G., Malojcic, G., Raunser, S. (2020) Structural basis of TRPC4 regulation by calmodulin and pharmacological agents. eLIFE. 9:.
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 (CaM). Molecular details of both CaM and drug binding have remained elusive so far. Here, we report structures of TRPC4 in complex with three pyridazinone-based inhibitors and CaM. 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. CaM 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 CaM-induced regulatory mechanism of canonical TRP channels.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping