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

Abstract

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-Å 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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Figure 1: Formation of the capsaicin-binding pocket.
Figure 2: VDW interactions between the tail and channel.
Figure 3: The tail is flexible and forms nonspecific interactions with the channel.
Figure 4: The neck interacts specifically with T551.
Figure 5: The head makes specific interactions with channel residues at the lipid-water interface.
Figure 6: Mechanism for capsaicin-induced channel activation.

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Acknowledgements

We thank members of the Zheng laboratory for assistance and constructive discussion. This work was supported by funding from National Institutes of Health (R01NS072377) and National Natural Science Foundation of China (31328011) to J.Z., National Natural Science Foundation of China (31328011, 81301720) to W.C., National Basic Research Program of China (2013CB910204), National Natural Science Foundation of China (81371302), China Scholarship Council to W.Y. and American Heart Association (14POST19820027) to F.Y.

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F.Y. and X.X. conducted most of experiments including molecular docking, patch-clamp recordings and data analysis; W.Y., P.Y., Z.S. and W.C. synthesized and analyzed capsaicin analogs; V.Y.-Y. supervised molecular docking and revised the manuscript; J.Z. and F.Y. prepared the manuscript; J.Z. conceived and supervised the project and participated in data analysis.

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Correspondence to Jie Zheng.

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Capsaicin binding and induced conformational changes to activate TRPV1 (MOV 9592 kb)

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Yang, F., Xiao, X., Cheng, W. et al. Structural mechanism underlying capsaicin binding and activation of the TRPV1 ion channel. Nat Chem Biol 11, 518–524 (2015). https://doi.org/10.1038/nchembio.1835

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