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TitleStructural basis of TRPV5 channel inhibition by econazole revealed by cryo-EM.
Journal, issue, pagesNat Struct Mol Biol, Vol. 25, Issue 1, Page 53-60, Year 2018
Publish dateJan 1, 2018
AuthorsTaylor 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 /
PubMed AbstractThe 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 ...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.
External linksNat Struct Mol Biol / PubMed:29323279 / PubMed Central
MethodsEM (single particle)
Resolution4.8 Å
Structure data

7058

6b5v

EMDB-7058, PDB-6b5v:
Structure of TRPV5 in complex with econazole
Method: EM (single particle) / Resolution: 4.8 Å

Chemicals

ChemComp-ECL:
1-[(2R)-2-[(4-chlorobenzyl)oxy]-2-(2,4-dichlorophenyl)ethyl]-1H-imidazole

ChemComp-CA:
Unknown entry

Source
  • oryctolagus cuniculus (rabbit)
KeywordsMEMBRANE PROTEIN / TRPV5 / Econazole / Transient Receptor Potential Channel / Cryo-EM

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