Molecular mechanisms underlying menthol binding and activation of TRPM8 ion channel.
Nat Commun, 2020/07/29;11(1):3790.
Xu L[1], Han Y[2, 3], Chen X[1], Aierken A[1], Wen H[4], Zheng W[4], Wang H[5, 6], Lu X[2, 3], Zhao Z[1], Ma C[7], Liang P[5, 6], Yang W[8], Yang S[9], Yang F[10]
Affiliations
PMID: 32728032DOI: 10.1038/s41467-020-17582-x
Impact factor: 17.694
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 Φ 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.
MeSH terms
Binding Sites; HEK293 Cells; Humans; Ion Channel Gating; Menthol; Molecular Docking Simulation; Molecular Dynamics Simulation; Mutagenesis; Patch-Clamp Techniques; Point Mutation; Protein Binding; Recombinant Proteins; Structure-Activity Relationship; TRPM Cation Channels
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