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

Authors :
Murray MH
Valfort AC
Koelblen T
Ronin C
Ciesielski F
Chatterjee A
Veerakanellore GB
Elgendy B
Walker JK
Hegazy L
Burris TP
Source :
Nature communications [Nat Commun] 2022 Nov 21; Vol. 13 (1), pp. 7131. Date of Electronic Publication: 2022 Nov 21.
Publication Year :
2022

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.<br /> (© 2022. The Author(s).)

Details

Language :
English
ISSN :
2041-1723
Volume :
13
Issue :
1
Database :
MEDLINE
Journal :
Nature communications
Publication Type :
Academic Journal
Accession number :
36414641
Full Text :
https://doi.org/10.1038/s41467-022-34892-4