Srivastava, ShriyanshShriyanshSrivastavaVishnu, A. M.A. M.VishnuThakur, RakeshRakeshThakurSrivastava, AshutoshAshutoshSrivastava2025-08-312025-08-312025-01-0110.1002/prot.268412-s2.0-105006579360https://d8.irins.org/handle/IITG2025/2830940418107REV-ERBβ is a nuclear receptor (NR) with heme as an endogenous ligand that regulates its transcriptional activity. With a key role in cellular functions such as glucose metabolism, immune response, and dysregulation in pathologies such as Type-2 diabetes mellitus and obesity, small molecule agonists and antagonists targeting REV-ERBs have been discovered. However, due to a lack of crystal structures in complex with these compounds, the structural and dynamical basis of these activities still remains elusive and hinders the rational design of molecules targeting REV-ERB. Using molecular dynamics simulations and docking studies, we have characterized the dynamics of REV-ERBβ ligand-binding domain (LBD) in different conformational states. The presence of heme in the binding pocket within LBD was found to dampen its dynamics as well as nuclear co-repressor (NCoR) peptide binding. We further show that the binding of the antagonist destabilizes the NCoR peptide binding to LBD mediated by loss of interactions with residues at the NCoR-REV-ERBβ interface. These findings could be utilized to design molecular scaffolds with better activity and selectivity against REV-ERBβ.falsecircadian rhythms | molecular dynamics simulation | NR1D2 | nuclear receptors | protein contact network | REV-ERBβArticle1097013420250arJournal0WOS:001494507300001