The vanilloid binding pocket of the TRPV1 channel. (A) Side view of the TRPV1 channel bound to a capsaicin molecule (red) embedded in a POPC lipid bilayer in an 140-Å periodic box containing 100 mM KCl. (B) Chemical structure of capsaicin. (C) The right image shows the lowest energy conformation (∆G = −7.2 kcal⋅mol⁻¹) from 50 independent docking simulations of capsaicin into the vanilloid binding pocket of TRPV1 (Protein Data Bank ID 3J5Q), where residues involved in capsaicin binding (Y511, T550, and E570) are pointed by arrows. (D) Chemical structure of CPZ. (E) CPZ into the vanilloid binding pocket of TRPV1 (Protein Data Bank ID 5IS0), where residues involved in CPZ binding I514 and V518 in S3 and M547 are denoted with arrows. (F) The left image is the chemical structure of RTX. (G) RTX into the vanilloid binding pocket of TRPV1 (Protein Data Bank ID 5IRX). Transmembrane segments of the TRPV1 channel are color coded as follows: S3, light blue; S4, green; S4 to S5 linker, purple; and S6, blue.

Binding of DkTx to the TRPV1 channel. (A) Side view of the TRPV1 channel bound to DkTx (K1 lobe and linker in green and K2 lobe in light blue) embedded in a POPC lipid bilayer in a 1400-Å periodic box containing 100 mM KCl. (B ) Upper view of the system shown in (A). (C) Closer view of the K1 lobe and the K1 to K2 linker (green), where the key residues in toxin binding are shown in licorice representation and labeled in light blue. Residues at the channel shown to be involved in DkTx-mediated channel opening are colored in red. (D) Closer view of the K2 lobe (light blue), where the key residues in toxin binding are shown in the licorice representation (light blue). Residues at the channel shown to be involved in DkTx-mediated channel opening are colored in red.