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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, Lü W
Nat Struct Mol Biol 28 604-613 (2021)
Related entries: 7mbp, 7mbq, 7mbr, 7mbs, 7mbt, 7mbv

Cited: 26 times
EuropePMC logo PMID: 34168372

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.

Articles - 7mbu mentioned but not cited (2)

  1. 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, Lü W. Nat Struct Mol Biol 28 604-613 (2021)
  2. Conservation of the cooling agent binding pocket within the TRPM subfamily. Huffer K, Denley MCS, Oskoui EV, Swartz KJ. bioRxiv 2024.05.20.595003 (2024)


Reviews citing this publication (10)

  1. TRP (transient receptor potential) ion channel family: structures, biological functions and therapeutic interventions for diseases. Zhang M, Ma Y, Ye X, Zhang N, Pan L, Wang B. Signal Transduct Target Ther 8 261 (2023)
  2. Sensory TRP Channels in Three Dimensions. Diver MM, Lin King JV, Julius D, Cheng Y. Annu Rev Biochem 91 629-649 (2022)
  3. Ligand-Binding Sites in Vanilloid-Subtype TRP Channels. Yelshanskaya MV, Sobolevsky AI. Front Pharmacol 13 900623 (2022)
  4. TRPM channels in health and disease. Chubanov V, Köttgen M, Touyz RM, Gudermann T. Nat Rev Nephrol 20 175-187 (2024)
  5. Targeting TRP channels: recent advances in structure, ligand binding, and molecular mechanisms. Huang J, Korsunsky A, Yazdani M, Chen J. Front Mol Neurosci 16 1334370 (2023)
  6. Thermal gradient ring for analysis of temperature-dependent behaviors involving TRP channels in mice. Ujisawa T, Lei J, Kashio M, Tominaga M. J Physiol Sci 74 9 (2024)
  7. Molecular determinants of TRPM8 function: key clues for a cool modulation. Pertusa M, Solorza J, Madrid R. Front Pharmacol 14 1213337 (2023)
  8. On the Connections between TRPM Channels and SOCE. Souza Bomfim GH, Niemeyer BA, Lacruz RS, Lis A. Cells 11 1190 (2022)
  9. Interaction of Calmodulin with TRPM: An Initiator of Channel Modulation. Vydra Bousova K, Zouharova M, Jiraskova K, Vetyskova V. Int J Mol Sci 24 15162 (2023)
  10. Navigating the Controversies: Role of TRPM Channels in Pain States. Gandini MA, Zamponi GW. Int J Mol Sci 25 10284 (2024)

Articles citing this publication (14)



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