1. Biochemistry and Chemical Biology
  2. Structural Biology and Molecular Biophysics
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Cooperative cobinding of synthetic and natural ligands to the nuclear receptor PPARγ

  1. Jinsai Shang
  2. Richard Brust
  3. Sarah A Mosure
  4. Jared Bass
  5. Paola Munoz-Tello
  6. Hua Lin
  7. Travis S Hughes
  8. Miru Tang
  9. Qingfeng Ge
  10. Theodore M Kamekencka
  11. Douglas J Kojetin  Is a corresponding author
  1. The Scripps Research Institute, United States
  2. University of Montana, United States
  3. Southern Illinois University, United States
Research Article
  • Cited 26
  • Views 2,725
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Cite this article as: eLife 2018;7:e43320 doi: 10.7554/eLife.43320

Abstract

Crystal structures of peroxisome proliferator-activated receptor gamma (PPARγ) have revealed overlapping binding modes for synthetic and natural/endogenous ligands, indicating competition for the orthosteric pocket. Here we show that cobinding of a synthetic ligand to the orthosteric pocket can push natural and endogenous PPARγ ligands (fatty acids) out of the orthosteric pocket towards an alternate ligand-binding site near the functionally important omega (Ω) loop. X-ray crystallography, NMR spectroscopy, all-atom molecular dynamics simulations, and mutagenesis coupled to quantitative biochemical functional and cellular assays reveal that synthetic ligand and fatty acid cobinding can form a 'ligand link' to the Ω loop and synergistically affect the structure and function of PPARγ. These findings contribute to a growing body of evidence indicating ligand binding to nuclear receptors can be more complex than the classical one-for-one orthosteric exchange of a natural or endogenous ligand with a synthetic ligand.

Data availability

Crystal structures and diffraction data have been deposited in the PDB under accession codes 5UGM, 6AVI, 6AUG, 6MCZ, 6MD0, 6MD1, 6MD2, and 6MD4.

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Jinsai Shang

    Department of Integrative Structural and Computational Biology, The Scripps Research Institute, Jupiter, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8164-1544
  2. Richard Brust

    Department of Integrative Structural and Computational Biology, The Scripps Research Institute, Jupiter, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9200-1101
  3. Sarah A Mosure

    Department of Integrative Structural and Computational Biology, The Scripps Research Institute, Jupiter, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Jared Bass

    Department of Integrative Structural and Computational Biology, The Scripps Research Institute, Jupiter, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Paola Munoz-Tello

    Department of Integrative Structural and Computational Biology, The Scripps Research Institute, Jupiter, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Hua Lin

    Department of Molecular Medicine, The Scripps Research Institute, Jupiter, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Travis S Hughes

    Center for Biomolecular Structure and Dynamics, University of Montana, Missoula, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5764-5884
  8. Miru Tang

    Department of Chemistry and Biochemistry, Southern Illinois University, Carbondale, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Qingfeng Ge

    Department of Chemistry and Biochemistry, Southern Illinois University, Carbondale, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Theodore M Kamekencka

    Department of Molecular Medicine, The Scripps Research Institute, Jupiter, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Douglas J Kojetin

    Department of Integrative Structural and Computational Biology, The Scripps Research Institute, Jupiter, United States
    For correspondence
    dkojetin@scripps.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8058-6168

Funding

National Institute of Diabetes and Digestive and Kidney Diseases (R01DK101871)

  • Douglas J Kojetin

American Heart Association (16- POST27780018)

  • Richard Brust

National Science Foundation (1659594)

  • Sarah A Mosure

The Scripps Research Institute

  • Sarah A Mosure

National Institute of Diabetes and Digestive and Kidney Diseases (R00DK103116)

  • Travis S Hughes

National Institute of Diabetes and Digestive and Kidney Diseases (F32DK108442)

  • Richard Brust

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

Reviewing Editor

  1. John Kuriyan, University of California, Berkeley, United States

Publication history

  1. Received: November 3, 2018
  2. Accepted: December 18, 2018
  3. Accepted Manuscript published: December 21, 2018 (version 1)
  4. Version of Record published: January 3, 2019 (version 2)

Copyright

© 2018, Shang 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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