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

Nat Chem Biol. 2015 Jul;11(7):518-524. doi: 10.1038/nchembio.1835. Epub 2015 Jun 8.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Bacterial Proteins / chemistry
  • Bacterial Proteins / genetics
  • Capsaicin / chemistry*
  • Chickens
  • Cryoelectron Microscopy
  • Gene Expression
  • HEK293 Cells
  • Humans
  • Ion Channel Gating
  • Kinetics
  • Luminescent Proteins / chemistry
  • Luminescent Proteins / genetics
  • Mice
  • Molecular Docking Simulation
  • Molecular Sequence Data
  • Patch-Clamp Techniques
  • Point Mutation
  • Protein Binding
  • Rabbits
  • Rats
  • Recombinant Fusion Proteins / chemistry
  • Recombinant Fusion Proteins / genetics
  • Sequence Alignment
  • Sequence Homology, Amino Acid
  • Species Specificity
  • TRPV Cation Channels / agonists*
  • TRPV Cation Channels / chemistry*
  • TRPV Cation Channels / genetics


  • Bacterial Proteins
  • Luminescent Proteins
  • Recombinant Fusion Proteins
  • TRPV Cation Channels
  • TRPV1 protein, mouse
  • yellow fluorescent protein, Bacteria
  • Capsaicin

Associated data

  • PubChem-Substance/251855291
  • PubChem-Substance/251855292
  • PubChem-Substance/251855293
  • PubChem-Substance/251855294
  • PubChem-Substance/251855295
  • PubChem-Substance/251855296
  • PubChem-Substance/251855297
  • PubChem-Substance/251855298
  • PubChem-Substance/251855299