Figure 6. Mechanistic models for TRPV1 activation.

a, Proposed mechanism for DkTx action. Two hydrophobic fingers (purple and pink) of each ICK knot (joined by three intramolecular disulfide bonds, yellow lines) enable the toxin to partition into the lipid bilayer (grey shade) and subsequently target TRPV1. In the closed state, the upper pore region of the channel (orange, pore helix; thick line, pore loop) undergoes brief spontaneous excursions to an open state, enabling DkTx to dock. Several annular lipids (blue ellipse with zigzag tails) bind at the channel-toxin interface to further stabilize the open state through formation of a tripartite complex. Resident phosphatidylinositides (blue hexagon attached to red sphere with zigzag tails) in the vanilloid pocket may leave upon toxin binding to facilitate allosteric opening of the lower gate. b, Proposed mechanism for vanilloid agonist action. Phosphatidylinositide co-factor binds in vanilloid pocket to stabilize the channel in its closed state. Vanilloid agonist (red hexagon attached to grey ellipse) displaces phosphatidylinositide to facilitate formation of a salt bridge between Arg557 (dark blue branch) and Glu570 (red branch), consequently pulling the S4–S5 linker away from the channel’s central axis to open the lower gate. c, Heat may open the channel through a similar mechanism involving thermal displacement of resident phosphatidylinositides.