Structural mechanism underlying capsaicin binding and activation of the TRPV1 ion channel

摘要: Capsaicin bestows spiciness by activating TRPV1 channel with exquisite potency and selectivity. Although a capsaicin-bound structure was previously resolved cryo-EM at 4.2- to 4.5-A resolution, capsaicin registered as small electron density, reflecting neither its chemical nor specific ligand-channel interactions--important details required for mechanistic understanding. We obtained the missing atomic-level iterative computation confirmed them systematic site-specific functional tests. observed that bound takes 'tail-up, head-down' configuration. The vanillyl amide groups form interactions anchor position, while aliphatic tail may sample range of conformations, making it invisible in images. stabilizes TRPV1's open state 'pull-and-contact' between group S4-S5 linker. Our study provides structural mechanism agonistic function analogs, demonstrates an effective approach obtain information from structures.