Structural basis of synthetic agonist activation of the nuclear receptor REV-ERB
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Nov 21, 2022
- Source ID
- 10.1038/s41467-022-34892-4
Entities
People
- Arindam Chatterjee
- Aurore Cecile Valfort
- Bahaa Elgendy
- Céline Ronin
- Fabrice Ciesielski
- Giri Babu Veerakanellore
- John K. Walker
- Lamees Hegazy
- Meghan H. Murray
- Thomas Burris
- Thomas Koelblen
Organizations
- National Institutes of Health
- United States Department of Defense