Structural basis of TRPV5 channel inhibition by econazole revealed by cryo-EM

Nat Struct Mol Biol. 2018 Jan;25(1):53-60. doi: 10.1038/s41594-017-0009-1. Epub 2018 Jan 1.


The transient receptor potential vanilloid 5 (TRPV5) channel is a member of the transient receptor potential (TRP) channel family, which is highly selective for Ca2+, that is present primarily at the apical membrane of distal tubule epithelial cells in the kidney and plays a key role in Ca2+ reabsorption. Here we present the structure of the full-length rabbit TRPV5 channel as determined using cryo-EM in complex with its inhibitor econazole. This structure reveals that econazole resides in a hydrophobic pocket analogous to that occupied by phosphatidylinositides and vanilloids in TRPV1, thus suggesting conserved mechanisms for ligand recognition and lipid binding among TRPV channels. The econazole-bound TRPV5 structure adopts a closed conformation with a distinct lower gate that occludes Ca2+ permeation through the channel. Structural comparisons between TRPV5 and other TRPV channels, complemented with molecular dynamics (MD) simulations of the econazole-bound TRPV5 structure, allowed us to gain mechanistic insight into TRPV5 channel inhibition by small molecules.

Publication types

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

MeSH terms

  • Animals
  • Calcium / chemistry
  • Cell Membrane / chemistry
  • Cryoelectron Microscopy*
  • Econazole / pharmacology*
  • Epitopes / chemistry
  • Humans
  • Hydrophobic and Hydrophilic Interactions
  • Ions
  • Molecular Dynamics Simulation
  • Mutation
  • Phosphatidylinositols / chemistry
  • Protein Conformation
  • Rabbits
  • Rats
  • TRPV Cation Channels / antagonists & inhibitors*
  • TRPV Cation Channels / chemistry*
  • Xenopus laevis


  • Epitopes
  • Ions
  • Phosphatidylinositols
  • TRPV Cation Channels
  • TRPV5 protein, human
  • Econazole
  • Calcium