Journal
NATURE CHEMICAL BIOLOGY
Volume 11, Issue 7, Pages 518-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/NCHEMBIO.1835
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Funding
- National Institutes of Health [R01NS072377]
- National Natural Science Foundation of China [31328011, 81301720, 81371302]
- National Basic Research Program of China [2013CB910204]
- China Scholarship Council
- American Heart Association [14POST19820027]
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Capsaicin bestows spiciness by activating TRPV1 channel with exquisite potency and selectivity. Although a capsaicin-bound channel structure was previously resolved by cryo-EM at 4.2-to 4.5-angstrom resolution, capsaicin was registered as a small electron density, reflecting neither its chemical structure nor specific ligand-channel interactions-important details required for mechanistic understanding. We obtained the missing atomic-level details by iterative computation and confirmed them by systematic site-specific functional tests. We observed that the bound capsaicin takes a 'tail-up, head-down' configuration. The vanillyl and amide groups form specific interactions to anchor its bound position, while the aliphatic tail may sample a range of conformations, making it invisible in cryo-EM images. Capsaicin stabilizes TRPV1's open state by 'pull-and-contact' interactions between the vanillyl group and the S4-S5 linker. Our study provides a structural mechanism for the agonistic function of capsaicin and its analogs, and demonstrates an effective approach to obtain atomic-level information from cryo-EM structures.
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