title: 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.
authors.affiliation: Department of Physiology and Membrane Biology, University of California, Davis, California 95616, United States.
authors.forename: Fan
authors.initials: F
authors.lastname: Yang
authors.affiliation: Department of Physiology and Membrane Biology, University of California, Davis, California 95616, United States.
authors.forename: Xian
authors.initials: X
authors.lastname: Xiao
authors.affiliation: Institute of Cancer Stem Cell, Dalian Medical University, Dalian, Liaoning 116044, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Cheng
authors.affiliation: Institute of Neuroscience, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Yang
authors.affiliation: Department of Toxicology, School of Public health, Zhejiang University, Hangzhou, Zhejiang 310058, China.
authors.forename: Peilin
authors.initials: P
authors.lastname: Yu
authors.affiliation: Department of Chemistry, Zhejiang Sci-Tech University, Hangzhou, Zhejiang 310018, China.
authors.forename: Zhenzhen
authors.initials: Z
authors.lastname: Song
authors.affiliation: Department of Physiology and Membrane Biology, University of California, Davis, California 95616, United States.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Yarov-Yarovoy
authors.affiliation: Department of Physiology and Membrane Biology, University of California, Davis, California 95616, United States.
authors.forename: Jie
authors.initials: J
authors.lastname: Zheng
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001426:Bacterial Proteins / Q000737:chemistry / Q000235:genetics; D002211:Capsaicin / Q000737:chemistry*; D002645:Chickens; D020285:Cryoelectron Microscopy; D015870:Gene Expression; D057809:HEK293 Cells; D006801:Humans; D015640:Ion Channel Gating; D007700:Kinetics; D008164:Luminescent Proteins / Q000737:chemistry / Q000235:genetics; D051379:Mice; D062105:Molecular Docking Simulation; D008969:Molecular Sequence Data; D018408:Patch-Clamp Techniques; D017354:Point Mutation; D011485:Protein Binding; D011817:Rabbits; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D013045:Species Specificity; D050916:TRPV Cation Channels / Q000819:agonists* / Q000737:chemistry* / Q000235:genetics
chemical_list: D001426:Bacterial Proteins; D008164:Luminescent Proteins; D011993:Recombinant Fusion Proteins; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; C054562:yellow fluorescent protein, Bacteria; D002211:Capsaicin