Fig. 2. Comparison of the transmembrane domain in TRPM8 and TRPV1.

(A) View down the channel pore from the extracellular side. Dashed red lines indicate the selectivity filter and the pore loop linking the pore helix (PH) and S6 in TRPM8, which were not built in the structure due to the lack of well-resolved cryo-EM density in this region (see Figure S5B). In all panels, the “+” indicates the center of the four-fold symmetry axis. (B) Overlay of the pore domains of TRPM8 (red) and the apo TRPV1 (blue, PDB ID: 3J5P). The pore helix in TRPM8 is located farther away from the ion permeation pathway. (C) Comparison of the junction between S4 and S5. In TRPM8, S5 is straight and fully α-helical, and connected to S4 via a sharp turn, while an S4–S5 linker is identified in TRPV1. The overlay illustrates the differing arrangement of the domain swap between TRPM8 and TRPV1. (D to F) The non-α-helical features in the S4 (D), S5 (E) and S6 (F) of TRPV1 (blue) are absent in those of TRPM8 (red). The differences in tilt of helices originating at helical bending points are indicated with dashed lines. (G to H) Comparison of the pores of the TRPM8 and the apo TRPV1 channels, showing that the S6 gate in TRPM8 is formed by Leu⁹⁷³. (I) The S6 gate of the TRPM8 structure viewed from the intracellular side. Leu⁹⁷³ is shown in sphere representation.