Structure-based characterization of novel TRPV5 inhibitors

Transient receptor potential vanilloid 5 (TRPV5) is a highly calcium selective ion channel that acts as the rate-limiting step of calcium reabsorption in the kidney. The lack of potent, specific modulators of TRPV5 has limited the ability to probe the contribution of TRPV5 in disease phenotypes such...

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Bibliographic Details
Published in:eLife 2019-10, Vol.8
Main Authors: Hughes, Taylor Et, Del Rosario, John Smith, Kapoor, Abhijeet, Yazici, Aysenur Torun, Yudin, Yevgen, Fluck, 3rd, Edwin C, Filizola, Marta, Rohacs, Tibor, Moiseenkova-Bell, Vera Y
Format: Article
Language:English
Subjects:
Binding Sites
Calcium
Cryo-EM
Cryoelectron Microscopy
Electron microscopy
Electrophysiology
Enzyme Inhibitors - chemical synthesis
Enzyme Inhibitors - pharmacology
HEK293 Cells
Homeostasis
Humans
Hypercalcemia
inhibitors
ion channal
Ion channels
Lipids
Microscopy
Molecular Docking Simulation
Nephrolithiasis
Novels
Phenotypes
Physiological aspects
Protein Conformation
Proteins
Reabsorption
Structural Biology and Molecular Biophysics
structure-based virtual screening
Structure-function relationships
Transient receptor potential proteins
TRP channel
TRPV Cation Channels - antagonists & inhibitors
TRPV Cation Channels - chemistry
TRPV5
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Summary:Transient receptor potential vanilloid 5 (TRPV5) is a highly calcium selective ion channel that acts as the rate-limiting step of calcium reabsorption in the kidney. The lack of potent, specific modulators of TRPV5 has limited the ability to probe the contribution of TRPV5 in disease phenotypes such as hypercalcemia and nephrolithiasis. Here, we performed structure-based virtual screening (SBVS) at a previously identified TRPV5 inhibitor binding site coupled with electrophysiology screening and identified three novel inhibitors of TRPV5, one of which exhibits high affinity, and specificity for TRPV5 over other TRP channels, including its close homologue TRPV6. Cryo-electron microscopy of TRPV5 in the presence of the specific inhibitor and its parent compound revealed novel binding sites for this channel. Structural and functional analysis have allowed us to suggest a mechanism of action for the selective inhibition of TRPV5 and lay the groundwork for rational design of new classes of TRPV5 modulators.
ISSN:2050-084X
2050-084X
DOI:10.7554/eLife.49572