EMD-23746
Cryo-EM structure of zebrafish TRPM5 E337A mutant in the presence of 5 mM calcium (low calcium occupancy in the transmembrane domain)
EMD-23746
Single-particle
Deposition: 01/04/2021Map released: 07/07/2021
Last modified: 06/11/2024
Sample Organism:
Danio rerio
Sample: TRPM5 channel E337A mutant
Fitted models: 7mbt
Deposition Authors: Ruan Z
,
Lu W
Sample: TRPM5 channel E337A mutant
Fitted models: 7mbt
Deposition Authors: Ruan Z
,
Lu W
Structures of the TRPM5 channel elucidate mechanisms of activation and inhibition.
Ruan Z ,
Haley E ,
Orozco IJ,
Sabat M,
Myers R,
Roth R ,
Du J ,
Lu W
(2021) Nat Struct Mol Biol , 28 , 604 - 613
,
Haley E ,
Orozco IJ,
Sabat M,
Myers R,
Roth R ,
Du J ,
Lu W
(2021) Nat Struct Mol Biol , 28 , 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.
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.