Fig. 6: A proposed heat-sensing mechanism of TRPV1 involves the interaction between the S4 helix and the S4-S5 linker.

a Structure-based ligand-gated mechanism of TRPV1 is shown in cartoon (PDB ID: 5IRZ and 5IRX). In the resting state, an endogenous lipid (yellow) occludes the canonical vanilloid binding pocket, perturbing the interaction between the R557 in S4 and E570 in S4–S5 linker. As a vanilloid ligand, resiniferatoxin (RTx, orange), binds the S1–S4 domain, the cation–π interaction between R557 and Y554 is disrupted and R557 changes conformation to interact with E570, opening the lower gate. For visual clarity, S3 helix is omitted, and only one S1–S4 domain is shown. b The close-up views that show the interaction between Y554 and R557 in S4 helix in the resting state (left, highlighted in cyan circle), and the interaction between R557 and E570 in S4-S5 linker (right, shown in cyan circle). Our data suggest that the C-terminal end of the S4 helix undergoes heat-induced movements in this region and loses helicity. This model is analogous to the ligand activation mechanism and suggests an understanding for overlap between heat and ligand activation.