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

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

Author information

1
Department of Pharmacology, School of Medicine, Case Western Reserve University, Cleveland, OH, USA.
2
Department of Nutrition, School of Medicine, Case Western Reserve University, Cleveland, OH, USA.
3
California NanoSystems Institute, University of California, Los Angeles, Los Angeles, CA, USA.
4
Department of Pharmacology, Physiology and Neuroscience, New Jersey Medical School, Rutgers University, Newark, NJ, USA.
5
Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
6
Department of Physiology and Biophysics School of Medicine, Case Western Reserve University, Cleveland, OH, USA.
7
Pfizer Research and Development, Groton, CT, USA.
8
Department of Pharmacology, School of Medicine, Case Western Reserve University, Cleveland, OH, USA. vmb@pennmedicine.upenn.edu.
9
Department of Physiology and Biophysics School of Medicine, Case Western Reserve University, Cleveland, OH, USA. vmb@pennmedicine.upenn.edu.
10
Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. vmb@pennmedicine.upenn.edu.

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 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.

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