Structure-based characterization of novel TRPV5 inhibitors

  1. Taylor ET Hughes
  2. John Smith Del Rosario
  3. Abhijeet Kapoor
  4. Aysenur Torun Yazici
  5. Yevgen Yudin
  6. Edwin C Fluck
  7. Marta Filizola  Is a corresponding author
  8. Tibor Rohacs  Is a corresponding author
  9. Vera Y Moiseenkova-Bell  Is a corresponding author
  1. University of Pennsylvania, United States
  2. New Jersey Medical School, Rutgers University, United States
  3. Icahn School of Medicine at Mount Sinai, United States

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 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.

Data availability

The cryo-EM density maps and atomic coordinates of all structures presented in the text will be deposited into the Electron Microscopy Data Bank and Protein Data Bank under the following access codes: ZINC9155420-bound TRPV5 (PDB: 6PBF, EMB-20292); ZINC17988990-bound TRPV5 (PDB: 6PBE, EMB-20291).

The following data sets were generated

Article and author information

Author details

  1. Taylor ET Hughes

    Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. John Smith Del Rosario

    Department of Pharmacology, Physiology and Neuroscience, New Jersey Medical School, Rutgers University, Newark, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4947-5835
  3. Abhijeet Kapoor

    Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Aysenur Torun Yazici

    Department of Pharmacology, Physiology and Neuroscience, New Jersey Medical School, Rutgers University, Newark, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1715-0107
  5. Yevgen Yudin

    Department of Pharmacology, Physiology and Neuroscience, New Jersey Medical School, Rutgers University, Newark, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Edwin C Fluck

    Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7663-569X
  7. Marta Filizola

    Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, United States
    For correspondence
    marta.filizola@mssm.edu
    Competing interests
    The authors declare that no competing interests exist.
  8. Tibor Rohacs

    Department of Pharmacology, Physiology and Neuroscience, New Jersey Medical School, Rutgers University, Newark, United States
    For correspondence
    rohacsti@njms.rutgers.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3580-2575
  9. Vera Y Moiseenkova-Bell

    Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
    For correspondence
    vmb@pennmedicine.upenn.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0589-4053

Funding

National Institute of General Medical Sciences (R01GM103899)

  • Vera Y Moiseenkova-Bell

National Institute of General Medical Sciences (R01GM129357)

  • Vera Y Moiseenkova-Bell

National Institute of General Medical Sciences (R01GM093290)

  • Tibor Rohacs

National Institute of General Medical Sciences (R01GM131048)

  • Tibor Rohacs

National Institute of Neurological Disorders and Stroke (R01NSNS055159)

  • Tibor Rohacs

National Science Foundation (ACI-1053575)

  • Marta Filizola

National Science Foundation (MCB080077)

  • Marta Filizola

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Baron Chanda, University of Wisconsin-Madison, United States

Publication history

  1. Received: June 21, 2019
  2. Accepted: October 23, 2019
  3. Accepted Manuscript published: October 24, 2019 (version 1)
  4. Accepted Manuscript updated: October 25, 2019 (version 2)
  5. Version of Record published: November 6, 2019 (version 3)

Copyright

© 2019, Hughes et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Taylor ET Hughes
  2. John Smith Del Rosario
  3. Abhijeet Kapoor
  4. Aysenur Torun Yazici
  5. Yevgen Yudin
  6. Edwin C Fluck
  7. Marta Filizola
  8. Tibor Rohacs
  9. Vera Y Moiseenkova-Bell
(2019)
Structure-based characterization of novel TRPV5 inhibitors
eLife 8:e49572.
https://doi.org/10.7554/eLife.49572
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