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

Meghan H. Murray, Aurore Cecile Valfort, Thomas Koelblen, Céline Ronin, Fabrice Ciesielski, Arindam Chatterjee, Giri Babu Veerakanellore, Bahaa Elgendy, John K. Walker, Lamees Hegazy () and Thomas P. Burris ()
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Meghan H. Murray: Saint Louis University School of Medicine
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
Bahaa Elgendy: Washington University School of Medicine, 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
Thomas P. Burris: University of Florida Genetics Institute

Nature Communications, 2022, vol. 13, issue 1, 1-12

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-34892-4

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