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

Taylor E.T. Hughes, David T. Lodowski, Kevin W. Huynh, Aysenur Yazici, John Del Rosario, Abhijeet Kapoor, Sandip Basak, Amrita Samanta, Xu Han, Sudha Chakrapani, Z. Hong Zhou, Marta Filizola, Tibor Rohacs, Seungil Han, Vera Y. Moiseenkova-Bell

Research output: Contribution to journalArticlepeer-review

61 Scopus citations

Abstract

The transient receptor potential vanilloid 5 (TRPV5) channel is a member of the transient receptor potential (TRP) channel family, which is highly selective for Ca 2+ , that is present primarily at the apical membrane of distal tubule epithelial cells in the kidney and plays a key role in Ca 2+ 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 Ca 2+ 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.

Original languageEnglish (US)
Pages (from-to)53-60
Number of pages8
JournalNature Structural and Molecular Biology
Volume25
Issue number1
DOIs
StatePublished - Jan 1 2018

All Science Journal Classification (ASJC) codes

  • Structural Biology
  • Molecular Biology

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