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

  • Nat Commun. 2022 Nov 21;13(1):7131. doi: 10.1038/s41467-022-34892-4.
Meghan H Murray  1  2 ,  Aurore Cecile Valfort  3 ,  Thomas Koelblen  3 ,  Céline Ronin  4 ,  Fabrice Ciesielski  4 ,  Arindam Chatterjee  1 ,  Giri Babu Veerakanellore  2  5 ,  Bahaa Elgendy  2  5 ,  John K Walker  1 ,  Lamees Hegazy  6  7 ,  Thomas P Burris  8
Affiliations
  • 1. Department of Pharmacology and Physiology, Saint Louis University School of Medicine, St. Louis, MO, 63104, USA.
  • 2. Center for Clinical Pharmacology, Washington University School of Medicine, University of Health Sciences & Pharmacy, St. Louis, MO, 63110, USA.
  • 3. University of Florida Genetics Institute, Gainesville, FL, 32610, USA.
  • 4. NovAliX SAS, Strasbourg, France.
  • 5. Department of Pharmaceutical and Administrative Sciences, University of Health Sciences & Pharmacy, St. Louis, MO, 63110, USA.
  • 6. Center for Clinical Pharmacology, Washington University School of Medicine, University of Health Sciences & Pharmacy, St. Louis, MO, 63110, USA. [email protected].
  • 7. Department of Pharmaceutical and Administrative Sciences, University of Health Sciences & Pharmacy, St. Louis, MO, 63110, USA. [email protected].
  • 8. University of Florida Genetics Institute, Gainesville, FL, 32610, USA. [email protected].
PMID: 36414641 DOI: 10.1038/s41467-022-34892-4
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.

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