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

Area of Science:

• Biochemistry
• Molecular Biology
• Structural Biology

Background:

• REV-ERBβ, a nuclear receptor regulated by heme, plays a crucial role in glucose metabolism and immune responses.
• Dysregulation of REV-ERBβ is implicated in Type-2 diabetes mellitus and obesity.
• Small molecules targeting REV-ERBs exist, but structural insights for rational drug design are lacking.

Purpose of the Study:

• To characterize the dynamics of the REV-ERBβ ligand-binding domain (LBD) using computational methods.
• To elucidate the structural basis for heme and antagonist interactions with REV-ERBβ.
• To provide insights for the rational design of novel REV-ERBβ modulators.

Main Methods:

• Molecular dynamics (MD) simulations.
• Molecular docking studies.
• Analysis of ligand-receptor interactions and conformational changes.

Main Results:

• Heme binding within the REV-ERBβ LBD was observed to dampen its dynamics.
• Heme presence also reduced nuclear co-repressor (NCoR) peptide binding.
• Antagonist binding destabilized NCoR peptide interaction with REV-ERBβ LBD by disrupting interface residues.

Conclusions:

• The study provides a detailed dynamic characterization of REV-ERBβ LBD.
• Findings highlight the impact of heme and antagonists on REV-ERBβ conformation and function.
• These insights can guide the development of more effective and selective REV-ERBβ-targeting therapeutics.