Fig. 3: Specific interactions between menthol isopropyl legs and the channel probed with 3-methylcyclohexanol.
From: Molecular mechanisms underlying menthol binding and activation of TRPM8 ion channel
a Docking predicted that the isopropyl legs of menthol stand on hydrophobic residues through VDW interactions (dashed lines in black: C9 atom of menthol to CD1 atom of I846: 3.53 Å; C8 atom of menthol to CB atom of L843: 3.66 Å). b Chemical structures of menthol, 3-methylcyclohexanol lacking the isopropyl legs, and cyclohexanol where both the isopropyl and methyl moieties are missing compared to menthol. c The concentration–response curves of wild type and mutant such as I846V with either menthol or 3-methylcyclohexanol were measured with whole-cell patch-clamp recordings (n = 3–5). d Representative whole-cell patch-clamp recording showed that cyclohexanol up to 5 mM cannot activate TRPM8 channel. e, f For wild type and I846V channel, Kd and L values were calculated from the concentration–response curves in c (two-sided t-test, *p < 0.05; NS not statistically significant). g Summary of coupling energy measurements. Coupling energy value was calculated from the Kd values. Mutants showing a coupling energy larger than 1.5 kT (dashed line) were colored in red. Those with less energy were colored in different shades of blue. At least four independent trials were performed for each chemical at each concentration. h Spatial distribution of coupling energy values within the menthol-binding pocket. Color scheme is the same as in g. Color scale is in the unit of kT. All statistical data are given as mean ± s.e.m. Source data are provided as a Source Data file.
