6B5V

Structure of TRPV5 in complex with econazole

Summary for 6B5V

• Entry DOI: 10.2210/pdb6b5v/pdb
• EMDB information: 7058
• Descriptor: Transient receptor potential cation channel subfamily V member 5, 1-[(2R)-2-[(4-chlorobenzyl)oxy]-2-(2,4-dichlorophenyl)ethyl]-1H-imidazole, CALCIUM ION (3 entities in total)
• Functional Keywords: trpv5, econazole, transient receptor potential channel, cryo-em, membrane protein
• Biological source: Oryctolagus cuniculus (Rabbit)
• Total number of polymer chains: 4
• Total formula weight: 333165.44

Authors

Hughes, T.E.T.,Lodowski, D.T.,Huynh, K.W.,Yazici, A.,del Rosario, J.,Kapoor, A.,Basak, S.,Samanta, A.,Chakrapani, S.,Zhou, Z.H.,Filizola, M.,Rohacs, T.,Han, S.,Moiseenkova-Bell, V.Y. (deposition date: 2017-09-29, release date: 2017-12-27, Last modification date: 2024-03-13)

Primary citation

Hughes, T.E.T.,Lodowski, D.T.,Huynh, K.W.,Yazici, A.,Del Rosario, J.,Kapoor, A.,Basak, S.,Samanta, A.,Han, X.,Chakrapani, S.,Zhou, Z.H.,Filizola, M.,Rohacs, T.,Han, S.,Moiseenkova-Bell, V.Y.
Structural basis of TRPV5 channel inhibition by econazole revealed by cryo-EM.
Nat. Struct. Mol. Biol., 25:53-60, 2018

PubMed 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, that is present primarily at the apical membrane of distal tubule epithelial cells in the kidney and plays a key role in Ca 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 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.

PubMed: 29323279
DOI: 10.1038/s41594-017-0009-1

Experimental method

ELECTRON MICROSCOPY (4.8 Å)