ReferenceID 2401
Molecular mechanisms underlying menthol binding and activation of TRPM8 ion channel
Nat Commun
Menthol in mints elicits coolness sensation by selectively activating TRPM8 channel. Although structures of TRPM8 were determined in the apo and liganded states, the menthol-bounded state is unresolved. To understand how
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Record Fields
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- Reference Id
- 2401
- Evidence Id
- 18991
- Core Evidence Id
- 18991
- Source Reference Id
- 4826
- Herb2 Reference Id
- HBREF005623
- Subject Paper Key
- HBIN034745_32728032
- Pubmed Id
- 32728032
- Doi
- 10.1038/s41467-020-17582-x
- Paper Title
- Molecular mechanisms underlying menthol binding and activation of TRPM8 ion channel
- Paper Abstract
- Menthol in mints elicits coolness sensation by selectively activating TRPM8 channel. Although structures of TRPM8 were determined in the apo and liganded states, the menthol-bounded state is unresolved. To understand how menthol activates the channel, we docked menthol to the channel and systematically validated our menthol binding models with thermodynamic mutant cycle analysis. We observed that menthol uses its hydroxyl group as a hand to specifically grab with R842, and its isopropyl group as legs to stand on I846 and L843. By imaging with fluorescent unnatural amino acid, we found that menthol binding induces wide-spread conformational rearrangements within the transmembrane domains. By Phi analysis based on single-channel recordings, we observed a temporal sequence of conformational changes in the S6 bundle crossing and the selectivity filter leading to channel activation. Therefore, our study suggested a 'grab and stand' mechanism of menthol binding and how menthol activates TRPM8 at the atomic level.
- Journal
- Nat Commun
- Publish Year
- 2020
- Experiment Subject
- Experiment Type
- Animal Experiment
- Phenotype Related
- Paper Title Cn
- Paper Title En
- Molecular mechanisms underlying menthol binding and activation of TRPM8 ion channel
- Bilingual Status
- semi_complete