Journal
NATURE STRUCTURAL & MOLECULAR BIOLOGY
Volume 25, Issue 1, Pages 53-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41594-017-0009-1
Keywords
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Funding
- National Institutes of Health Core Grant [P30EY11373]
- Extreme Science and Engineering Discovery Environment [MCB080077]
- National Science Foundation [ACI-1053575]
- NIH [1S10RR23057, 1S10OD018111]
- NSF [DBI-1338135]
- CNSI at UCLA
- National Institute of Health [R01GM103899, R01GM093290, U24 GM116792]
- NATIONAL CENTER FOR RESEARCH RESOURCES [S10RR023057] Funding Source: NIH RePORTER
- NATIONAL EYE INSTITUTE [P30EY011373] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [T32AI060567] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R01GM129357, R01GM103899, R01GM108921, U24GM116792, R01GM093290] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R01NS055159] Funding Source: NIH RePORTER
- OFFICE OF THE DIRECTOR, NATIONAL INSTITUTES OF HEALTH [S10OD018522, S10OD018111] Funding Source: NIH RePORTER
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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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