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Structural basis of synthetic agonist activation of the nuclear receptor REV-ERB

Author

Listed:
  • Meghan H. Murray

    (Saint Louis University School of Medicine
    Washington University School of Medicine, University of Health Sciences & Pharmacy)

  • Aurore Cecile Valfort

    (University of Florida Genetics Institute)

  • Thomas Koelblen

    (University of Florida Genetics Institute)

  • Céline Ronin

    (NovAliX SAS)

  • Fabrice Ciesielski

    (NovAliX SAS)

  • Arindam Chatterjee

    (Saint Louis University School of Medicine)

  • Giri Babu Veerakanellore

    (Washington University School of Medicine, University of Health Sciences & Pharmacy
    University of Health Sciences & Pharmacy)

  • Bahaa Elgendy

    (Washington University School of Medicine, University of Health Sciences & Pharmacy
    University of Health Sciences & Pharmacy)

  • John K. Walker

    (Saint Louis University School of Medicine)

  • Lamees Hegazy

    (Washington University School of Medicine, University of Health Sciences & Pharmacy
    University of Health Sciences & Pharmacy)

  • Thomas P. Burris

    (University of Florida Genetics Institute)

Abstract

The nuclear receptor REV-ERB plays an important role in a range of physiological processes. REV-ERB behaves as a ligand-dependent transcriptional repressor and heme has been identified as a physiological agonist. Our current understanding of how ligands bind to and regulate transcriptional repression by REV-ERB is based on the structure of heme bound to REV-ERB. However, porphyrin (heme) analogues have been avoided as a source of synthetic agonists due to the wide range of heme binding proteins and potential pleotropic effects. How non-porphyrin synthetic agonists bind to and regulate REV-ERB has not yet been defined. Here, we characterize a high affinity synthetic REV-ERB agonist, STL1267, and describe its mechanism of binding to REV-ERB as well as the method by which it recruits transcriptional corepressor both of which are unique and distinct from that of heme-bound REV-ERB.

Suggested Citation

  • Meghan H. Murray & Aurore Cecile Valfort & Thomas Koelblen & Céline Ronin & Fabrice Ciesielski & Arindam Chatterjee & Giri Babu Veerakanellore & Bahaa Elgendy & John K. Walker & Lamees Hegazy & Thomas, 2022. "Structural basis of synthetic agonist activation of the nuclear receptor REV-ERB," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34892-4
    DOI: 10.1038/s41467-022-34892-4
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    References listed on IDEAS

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    1. Han Cho & Xuan Zhao & Megumi Hatori & Ruth T. Yu & Grant D. Barish & Michael T. Lam & Ling-Wa Chong & Luciano DiTacchio & Annette R. Atkins & Christopher K. Glass & Christopher Liddle & Johan Auwerx &, 2012. "Regulation of circadian behaviour and metabolism by REV-ERB-α and REV-ERB-β," Nature, Nature, vol. 485(7396), pages 123-127, May.
    2. Gabriele Sulli & Amy Rommel & Xiaojie Wang & Matthew J. Kolar & Francesca Puca & Alan Saghatelian & Maksim V. Plikus & Inder M. Verma & Satchidananda Panda, 2018. "Pharmacological activation of REV-ERBs is lethal in cancer and oncogene-induced senescence," Nature, Nature, vol. 553(7688), pages 351-355, January.
    3. Laura A. Solt & Yongjun Wang & Subhashis Banerjee & Travis Hughes & Douglas J. Kojetin & Thomas Lundasen & Youseung Shin & Jin Liu & Michael D. Cameron & Romain Noel & Seung-Hee Yoo & Joseph S. Takaha, 2012. "Regulation of circadian behaviour and metabolism by synthetic REV-ERB agonists," Nature, Nature, vol. 485(7396), pages 62-68, May.
    4. Laura A. Solt & Naresh Kumar & Philippe Nuhant & Yongjun Wang & Janelle L. Lauer & Jin Liu & Monica A. Istrate & Theodore M. Kamenecka & William R. Roush & Dušica Vidović & Stephan C. Schürer & Jihong, 2011. "Suppression of TH17 differentiation and autoimmunity by a synthetic ROR ligand," Nature, Nature, vol. 472(7344), pages 491-494, April.
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