TRPV1 structures in nanodiscs reveal mechanisms of ligand and lipid action

Nature. 2016 Jun 16;534(7607):347-51. doi: 10.1038/nature17964. Epub 2016 May 18.


When integral membrane proteins are visualized in detergents or other artificial systems, an important layer of information is lost regarding lipid interactions and their effects on protein structure. This is especially relevant to proteins for which lipids have both structural and regulatory roles. Here we demonstrate the power of combining electron cryo-microscopy with lipid nanodisc technology to ascertain the structure of the rat TRPV1 ion channel in a native bilayer environment. Using this approach, we determined the locations of annular and regulatory lipids and showed that specific phospholipid interactions enhance binding of a spider toxin to TRPV1 through formation of a tripartite complex. Furthermore, phosphatidylinositol lipids occupy the binding site for capsaicin and other vanilloid ligands, suggesting a mechanism whereby chemical or thermal stimuli elicit channel activation by promoting the release of bioactive lipids from a critical allosteric regulatory site.

Publication types

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

MeSH terms

  • Allosteric Site / drug effects
  • Amino Acid Sequence
  • Animals
  • Capsaicin / metabolism
  • Cryoelectron Microscopy
  • Ligands
  • Lipid Bilayers / chemistry
  • Lipid Bilayers / metabolism*
  • Membrane Proteins / chemistry
  • Membrane Proteins / drug effects
  • Membrane Proteins / metabolism
  • Membrane Proteins / ultrastructure
  • Molecular Sequence Data
  • Nanostructures / chemistry*
  • Nanostructures / ultrastructure
  • Phosphatidylinositol Phosphates / metabolism
  • Phospholipids / chemistry
  • Phospholipids / metabolism
  • Rats
  • Spider Venoms / chemistry
  • Spider Venoms / metabolism*
  • TRPV Cation Channels / chemistry*
  • TRPV Cation Channels / drug effects
  • TRPV Cation Channels / metabolism*
  • TRPV Cation Channels / ultrastructure
  • Temperature


  • Ligands
  • Lipid Bilayers
  • Membrane Proteins
  • Phosphatidylinositol Phosphates
  • Phospholipids
  • Spider Venoms
  • TRPV Cation Channels
  • Trpv1 protein, rat
  • Capsaicin