Investigating REV-ERBβ Binding Pocket Dynamics with Implications for Rational Design of Small Molecule Modulators

REV-ERBβ is a nuclear receptor (NR) with heme as an endogenous ligand that regulates its transcriptional activity. With key role in cellular functions in glucose metabolism, and immune response and dysregulation in pathologies such as Type-2 diabetes mellitus and obesity, small molecules targeting REV-ERBs have been discovered with agonist and antagonistic effect. However, due to lack of crystal structures in complex with these compounds, the structural and dynamical basis of these activities still remains elusive and hinders 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 heme binding pocket remained closed in absence of a ligand and heme was found to stabilize LBD dynamics as well as nuclear co-repressor (NCoR) peptide binding. We further show that the binding of 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.