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Structure paper

TitleMolecular basis for cold and menthol sensing by mammalian TRPM8.
Journal, issue, pagesNat Commun, Vol. 17, Issue 1, Year 2026
Publish dateAug 17, 2026
AuthorsHyuk-Joon Lee / Cheon-Gyu Park / Justin G Fedor / Wyatt A Peele / Mario J Borgnia / Seok-Yong Lee /
PubMed AbstractThe transient receptor potential melastatin member 8 (TRPM8) is a polymodal ion channel that senses cold and menthol in mammals. Despite prior structural studies, the mechanisms by which cold and ...The transient receptor potential melastatin member 8 (TRPM8) is a polymodal ion channel that senses cold and menthol in mammals. Despite prior structural studies, the mechanisms by which cold and menthol activate TRPM8 remain unresolved. Here, we present cryo-EM structures and extensive functional analyses to reveal cold- and menthol-dependent activation mechanisms. We observe that cold-sensing residues are widespread and that snapshots of cooling-dependent opening reveal dramatic pore rearrangement which suggest a mechanism for cold sensing. Menthol binds dynamically to drive channel activation toward a common gate with cold, but with specific outer pore conformations. Finally, we show how TRPM8 integrates cold and menthol modalities through overlapping but non-identical networks, revealing a coldspot that is central to cold activation of TRPM8 and is the location of allyl isothiocyanate (AITC) binding. These findings enhance our understanding of the molecular basis of physically and chemically induced cool sensation in mammals.
External linksNat Commun / PubMed:42744822 / PubMed Central
MethodsEM (single particle)
Resolution3.1 - 3.6 Å
Structure data

71916

9pwe

EMDB-71916, PDB-9pwe:
Menthol-bound mouse TRPM8 in complex with AITC and PIP2 in a closed (C1M') state
Method: EM (single particle) / Resolution: 3.4 Å

71917

9pwf

EMDB-71917, PDB-9pwf:
Menthol-bound mouse TRPM8-I846V in complex with PIP2 in an intermediate (C2M, 20C) state
Method: EM (single particle) / Resolution: 3.1 Å

71918

9pwg

EMDB-71918, PDB-9pwg:
The pre-open state (pre-OM, 20C), menthol-bound mouse TRPM8-I846V in complex with AITC and PIP2
Method: EM (single particle) / Resolution: 3.4 Å

71919

9pwh

EMDB-71919, PDB-9pwh:
AITC- and PIP2-bound mouse TRPM8 in a closed (C1A) state
Method: EM (single particle) / Resolution: 3.6 Å

72557

9y69

EMDB-72557, PDB-9y69:
The cold-intermediate state (C2M, 4C), menthol-bound mouse TRPM8-I846V in complex with AITC and PIP2
Method: EM (single particle) / Resolution: 3.3 Å

72558

9y6a

EMDB-72558, PDB-9y6a:
The cold-open state (OM, 4C), menthol-bound mouse TRPM8-I846V in complex with AITC and PIP2
Method: EM (single particle) / Resolution: 3.4 Å

74963

9zyr

EMDB-74963, PDB-9zyr:
Menthol-and PIP2-bound mouse TRPM8 in a closed (C1M) state
Method: EM (single particle) / Resolution: 3.6 Å

Chemicals

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-C14:
TETRADECANE

ChemComp-UL9:
3-isothiocyanatoprop-1-ene


ChemComp, No image

ChemComp-XUQ:
Unknown entry

Source
  • mus musculus (house mouse)
KeywordsMEMBRANE PROTEIN / TRPM8 / Menthol / Cold / Channel opening

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