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Nat Struct Mol Biol
2018 Jan 01;251:53-60. doi: 10.1038/s41594-017-0009-1.
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Structural basis of TRPV5 channel inhibition by econazole revealed by cryo-EM.
Hughes TET
,
Lodowski DT
,
Huynh KW
,
Yazici A
,
Del Rosario J
,
Kapoor A
,
Basak S
,
Samanta A
,
Han X
,
Chakrapani S
,
Zhou ZH
,
Filizola M
,
Rohacs T
,
Han S
,
Moiseenkova-Bell VY
.
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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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