PUBLICATION
Structures of the TRPM5 channel elucidate mechanisms of activation and inhibition
- Authors
- Ruan, Z., Haley, E., Orozco, I.J., Sabat, M., Myers, R., Roth, R., Du, J., Lü, W.
- ID
- ZDB-PUB-210629-3
- Date
- 2021
- Source
- Nature structural & molecular biology 28(7): 604-613 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- Animals
- Binding Sites/physiology
- Calcium/metabolism
- Cell Membrane/physiology*
- Cryoelectron Microscopy
- Enzyme Activation
- Humans
- Patch-Clamp Techniques
- Protein Conformation
- TRPM Cation Channels/antagonists & inhibitors
- TRPM Cation Channels/metabolism*
- Zebrafish/metabolism*
- PubMed
- 34168372 Full text @ Nat. Struct. Mol. Biol.
Citation
Ruan, Z., Haley, E., Orozco, I.J., Sabat, M., Myers, R., Roth, R., Du, J., Lü, W. (2021) Structures of the TRPM5 channel elucidate mechanisms of activation and inhibition. Nature structural & molecular biology. 28(7):604-613.
Abstract
The Ca2+-activated TRPM5 channel plays essential roles in taste perception and insulin secretion. However, the mechanism by which Ca2+ regulates TRPM5 activity remains elusive. We report cryo-EM structures of the zebrafish TRPM5 in an apo closed state, a Ca2+-bound open state, and an antagonist-bound inhibited state. We define two novel ligand binding sites: a Ca2+ site (CaICD) in the intracellular domain and an antagonist site in the transmembrane domain (TMD). The CaICD site is unique to TRPM5 and has two roles: modulating the voltage dependence and promoting Ca2+ binding to the CaTMD site, which is conserved throughout TRPM channels. Conformational changes initialized from both Ca2+ sites cooperatively open the ion-conducting pore. The antagonist NDNA wedges into the space between the S1-S4 domain and pore domain, stabilizing the transmembrane domain in an apo-like closed state. Our results lay the foundation for understanding the voltage-dependent TRPM channels and developing new therapeutic agents.
Errata / Notes
This article is corrected by ZDB-PUB-220906-255 . Correction: https://www.nature.com/articles/s41594-021-00641-2 Corrects Article: https://www.nature.com/articles/s41594-021-00607-4
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping