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Structures of the TRPM5 channel elucidate mechanisms of activation and inhibition
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Journal Article
Structures of the TRPM5 channel elucidate mechanisms of activation and inhibition
2021
Overview
The Ca
2+
-activated TRPM5 channel plays essential roles in taste perception and insulin secretion. However, the mechanism by which Ca
2+
regulates TRPM5 activity remains elusive. We report cryo-EM structures of the zebrafish TRPM5 in an apo closed state, a Ca
2+
-bound open state, and an antagonist-bound inhibited state. We define two novel ligand binding sites: a Ca
2+
site (Ca
ICD
) in the intracellular domain and an antagonist site in the transmembrane domain (TMD). The Ca
ICD
site is unique to TRPM5 and has two roles: modulating the voltage dependence and promoting Ca
2+
binding to the Ca
TMD
site, which is conserved throughout TRPM channels. Conformational changes initialized from both Ca
2+
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.
Cryo-EM structures of zebrafish TRPM5 reveal closed and Ca
2+
-bound open states, a unique Ca
2+
binding site that modulates voltage sensitivity and the mechanism of antagonist action.
Publisher
Nature Publishing Group US,Nature Publishing Group
Subject
/ 82/83
/ 9/74
/ Animals
/ Binding sites (Biochemistry)
/ Biomedical and Life Sciences
/ Calcium channels (voltage-gated)
/ Channels
/ Domains
/ Humans
/ Insulin
/ Taste
/ Transient receptor potential proteins
/ TRPM Cation Channels - antagonists & inhibitors
/ TRPM Cation Channels - metabolism
/ Voltage
