Structures of the TRPM5 channel elucidate mechanisms of activation and inhibition

Zheng Ruan; Emery Haley; Ian J. Orozco; Mark Sabat; Richard Myers; Rebecca Roth; Juan Du; Wei Lü

doi:10.1038/s41594-021-00607-4

Structures of the TRPM5 channel elucidate mechanisms of activation and inhibition

Zheng Ruan, Emery Haley, Ian J. Orozco, Mark Sabat, Richard Myers, Rebecca Roth, Juan Du^*, Wei Lü^*

^*Corresponding author for this work

Molecular Biosciences

Research output: Contribution to journal › Article › peer-review

39 Scopus citations

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 (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 Ca²⁺ binding to the Ca_TMD 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.

Original language	English (US)
Pages (from-to)	604-613
Number of pages	10
Journal	Nature Structural and Molecular Biology
Volume	28
Issue number	7
DOIs	https://doi.org/10.1038/s41594-021-00607-4
State	Published - Jul 2021

Funding

We thank G. Zhao and X. Meng for support with data collection at the David Van Andel Advanced Cryo-Electron Microscopy Suite. We appreciate the high-performance computing team of VAI for computational support. We thank D. Nadziejka and M. Martin for technical editing. W.L. is supported by National Institutes of Health (NIH) grants (R56HL144929, R01HL153219 and R01NS112363). J.D. is supported by a McKnight Scholar Award, a Klingenstein–Simon Scholar Award, a Sloan Research Fellowship in neuroscience, a Pew Scholar in the Biomedical Sciences award and an NIH grant (R01NS111031). Z.R. is supported by an American Heart Association postdoctoral fellowship (20POST35120556).

ASJC Scopus subject areas

Structural Biology
Molecular Biology

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title = "Structures of the TRPM5 channel elucidate mechanisms of activation and inhibition",

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.",

author = "Zheng Ruan and Emery Haley and Orozco, \{Ian J.\} and Mark Sabat and Richard Myers and Rebecca Roth and Juan Du and Wei L{\"u}",

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AU - Ruan, Zheng

AU - Haley, Emery

AU - Orozco, Ian J.

AU - Sabat, Mark

AU - Myers, Richard

AU - Roth, Rebecca

AU - Du, Juan

AU - Lü, Wei

PY - 2021/7

Y1 - 2021/7

N2 - 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.

AB - 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.

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Structures of the TRPM5 channel elucidate mechanisms of activation and inhibition

Abstract

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