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TitleStructural basis of cooling agent and lipid sensing by the cold-activated TRPM8 channel.
Journal, issue, pagesScience, Vol. 363, Issue 6430, Year 2019
Publish dateMar 1, 2019
AuthorsYing Yin / Son C Le / Allen L Hsu / Mario J Borgnia / Huanghe Yang / Seok-Yong Lee /
PubMed AbstractTransient receptor potential melastatin member 8 (TRPM8) is a calcium ion (Ca)-permeable cation channel that serves as the primary cold and menthol sensor in humans. Activation of TRPM8 by cooling ...Transient receptor potential melastatin member 8 (TRPM8) is a calcium ion (Ca)-permeable cation channel that serves as the primary cold and menthol sensor in humans. Activation of TRPM8 by cooling compounds relies on allosteric actions of agonist and membrane lipid phosphatidylinositol 4,5-bisphosphate (PIP), but lack of structural information has thus far precluded a mechanistic understanding of ligand and lipid sensing by TRPM8. Using cryo-electron microscopy, we determined the structures of TRPM8 in complex with the synthetic cooling compound icilin, PIP, and Ca, as well as in complex with the menthol analog WS-12 and PIP Our structures reveal the binding sites for cooling agonists and PIP in TRPM8. Notably, PIP binds to TRPM8 in two different modes, which illustrate the mechanism of allosteric coupling between PIP and agonists. This study provides a platform for understanding the molecular mechanism of TRPM8 activation by cooling agents.
External linksScience / PubMed:30733385 / PubMed Central
MethodsEM (single particle)
Resolution3.4 - 4.3 Å
Structure data

0487

6nr2

EMDB-0487, PDB-6nr2:
Cryo-EM structure of the TRPM8 ion channel in complex with the menthol analog WS-12 and PI(4,5)P2
Method: EM (single particle) / Resolution: 4.0 Å

0488

6nr3

EMDB-0488, PDB-6nr3:
Cryo-EM structure of the TRPM8 ion channel in complex with high occupancy icilin, PI(4,5)P2, and calcium
Method: EM (single particle) / Resolution: 3.4 Å

0489

6nr4

EMDB-0489, PDB-6nr4:
Cryo-EM structure of the TRPM8 ion channel with low occupancy icilin, PI(4,5)P2, and calcium
Method: EM (single particle) / Resolution: 4.3 Å

Chemicals

ChemComp-KXP:
(2S)-1-{[(R)-hydroxy{[(1R,2R,3S,4R,5R,6S)-2,3,6-trihydroxy-4,5-bis(phosphonooxy)cyclohexyl]oxy}phosphoryl]oxy}-3-(octadecanoyloxy)propan-2-yl icosa-5,8,11,14-tetraenoate

ChemComp-KXS:
(1R,2S,5R)-N-(4-methoxyphenyl)-5-methyl-2-(propan-2-yl)cyclohexane-1-carboxamide

ChemComp-KX7:
Icilin / agonist*YM

ChemComp-CA:
Unknown entry

Source
  • ficedula albicollis (Collared flycatcher)
KeywordsTRANSPORT PROTEIN / ion channel / TRP channel / TRPM channel / TRPM8 channel / cold sensing / lipid sensing / menthol / icilin / WS-12 / PI(4 / 5)P2 / cooling agent / MEMBRANE PROTEIN / calcium-permeable ion channel / calcium-permeable channel

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