6PBE

ZINC17988990-bound TRPV5 in nanodiscs


Experimental Data Snapshot

  • Method: ELECTRON MICROSCOPY
  • Resolution: 3.78 Å
  • Aggregation State: PARTICLE 
  • Reconstruction Method: SINGLE PARTICLE 

wwPDB Validation 3D Report Full Report


This is version 1.0 of the entry. See complete history

Literature

Structure-based characterization of novel TRPV5 inhibitors.

Hughes, T.E.Del Rosario, J.S.Kapoor, A.Yazici, A.T.Yudin, Y.Fluck, E.C.Filizola, M.Rohacs, T.Moiseenkova-Bell, V.Y.

(2019) Elife 8: --

  • DOI: 10.7554/eLife.49572
  • Primary Citation of Related Structures:  

  • PubMed Abstract: 
  • 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 th ...

    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.


    Organizational Affiliation

    Department of Pharmacology, Physiology and Neuroscience, New Jersey Medical School, Rutgers University, Newark, United States.,Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, United States.,Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States.




Macromolecules

Find similar proteins by: Sequence  |  Structure

Entity ID: 1
MoleculeChainsSequence LengthOrganismDetails
Transient receptor potential cation channel subfamily V member 5
A, B, C, D
730Oryctolagus cuniculusMutation(s): 0 
Gene Names: Trpv5 (Ecac1)
Find proteins for Q9XSM3 (Oryctolagus cuniculus)
Go to UniProtKB:  Q9XSM3
Small Molecules
Ligands 1 Unique
IDChainsName / Formula / InChI Key2D Diagram3D Interactions
O6S
Query on O6S

Download SDF File 
Download CCD File 
A, B, C, D
(4-oxo-5-phenyl-3,4-dihydrothieno[2,3-d]pyrimidin-2-yl)methyl 3-(3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)propanoate
C24 H19 N3 O5 S
YOFCRYWWKQMPEW-UHFFFAOYSA-N
 Ligand Interaction
Experimental Data & Validation

Experimental Data

  • Method: ELECTRON MICROSCOPY
  • Resolution: 3.78 Å
  • Aggregation State: PARTICLE 
  • Reconstruction Method: SINGLE PARTICLE 

Structure Validation

View Full Validation Report or Ramachandran Plots



Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Institutes of Health/National Institute of General Medical SciencesR01GM103899
National Institutes of Health/National Institute of General Medical SciencesR01GM129357
National Institutes of Health/National Institute of General Medical SciencesR01GM093290

Revision History 

  • Version 1.0: 2019-11-06
    Type: Initial release