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TitleActivation mechanism of the mouse cold-sensing TRPM8 channel by cooling agonist and PIP.
Journal, issue, pagesScience, Vol. 378, Issue 6616, Page eadd1268, Year 2022
Publish dateOct 14, 2022
AuthorsYing Yin / Feng Zhang / Shasha Feng / Kevin John Butay / Mario J Borgnia / Wonpil Im / Seok-Yong Lee /
PubMed AbstractThe transient receptor potential melastatin 8 (TRPM8) channel is the primary molecular transducer responsible for the cool sensation elicited by menthol and cold in mammals. TRPM8 activation is ...The transient receptor potential melastatin 8 (TRPM8) channel is the primary molecular transducer responsible for the cool sensation elicited by menthol and cold in mammals. TRPM8 activation is controlled by cooling compounds together with the membrane lipid phosphatidylinositol 4,5-bisphosphate (PIP). Our knowledge of cold sensation and the therapeutic potential of TRPM8 for neuroinflammatory diseases and pain will be enhanced by understanding the structural basis of cooling agonist- and PIP-dependent TRPM8 activation. We present cryo-electron microscopy structures of mouse TRPM8 in closed, intermediate, and open states along the ligand- and PIP-dependent gating pathway. Our results uncover two discrete agonist sites, state-dependent rearrangements in the gate positions, and a disordered-to-ordered transition of the gate-forming S6-elucidating the molecular basis of chemically induced cool sensation in mammals.
External linksScience / PubMed:36227998 / PubMed Central
MethodsEM (single particle)
Resolution3.07 - 3.59 Å
Structure data

EMDB-27889: Mouse TRPM8 structure determined in the ligand- and PI(4,5)P2-free condition, Class II, C1 state with endogenous PI(4,5)P2 bound
Method: EM (single particle) / Resolution: 3.13 Å

EMDB-27890: Mouse TRPM8 structure determined in the ligand- and PI(4,5)P2-free condition, Class III, putative desensitized state
Method: EM (single particle) / Resolution: 3.43 Å

EMDB-27891, PDB-8e4l:
The open state mouse TRPM8 structure in complex with the cooling agonist C3, AITC, and PI(4,5)P2
Method: EM (single particle) / Resolution: 3.32 Å

EMDB-27892, PDB-8e4m:
The intermediate C2-state mouse TRPM8 structure in complex with the cooling agonist C3 and PI(4,5)P2
Method: EM (single particle) / Resolution: 3.44 Å

EMDB-27893, PDB-8e4n:
The closed C1-state mouse TRPM8 structure in complex with PI(4,5)P2
Method: EM (single particle) / Resolution: 3.07 Å

EMDB-27894, PDB-8e4o:
The closed C1-state mouse TRPM8 structure in complex with putative PI(4,5)P2
Method: EM (single particle) / Resolution: 3.43 Å

EMDB-27895, PDB-8e4p:
Mouse TRPM8 structure determined in the ligand- and PI(4,5)P2-free condition, Class I , C0 state
Method: EM (single particle) / Resolution: 3.59 Å

EMDB-27896, PDB-8e4q:
The closed C0-state flycatcher TRPM8 structure in complex with PI(4,5)P2
Method: EM (single particle) / Resolution: 3.51 Å

Chemicals

ChemComp-CA:
Unknown entry

ChemComp-UL9:
3-isothiocyanatoprop-1-ene / Allyl isothiocyanate

ChemComp-ULO:
nonyl(oxo)di(propan-2-yl)-lambda~5~-phosphane

ChemComp-PIO:
[(2R)-2-octanoyloxy-3-[oxidanyl-[(1R,2R,3S,4R,5R,6S)-2,3,6-tris(oxidanyl)-4,5-diphosphonooxy-cyclohexyl]oxy-phosphoryl]oxy-propyl] octanoate

ChemComp-Y01:
CHOLESTEROL HEMISUCCINATE

Source
  • mus musculus (house mouse)
  • Mus musculus
  • ficedula albicollis (Collared flycatcher)
KeywordsMEMBRANE PROTEIN / TRPM8 / menthol receptor / cold receptor / PI(4 / 5)P2 / cooling agonists / temperature sensing / ion channel / sensory transduction / transient receptor potential ion channel / cold sensor

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