Exposing Hidden Binding Pockets in Cereblon: His378 Conformational Dynamics Inform Novel Ligand Design

Area of Science:

• Biochemistry
• Structural Biology
• Drug Discovery

Background:

• Cereblon (CRBN) is crucial for CRL4 ubiquitin ligase complex function and substrate degradation.
• CRBN ligands are vital for targeted protein degradation therapies like PROTACs and molecular glues.
• Existing CRBN ligands face limitations in selectivity and intellectual property, necessitating novel chemotypes.

Purpose of the Study:

• To investigate the conformational dynamics of the CRBN ligand-binding pocket.
• To identify novel binding opportunities for CRBN ligand design.
• To provide a structural basis for next-generation CRBN binders.

Main Methods:

• Extensive molecular dynamics (MD) simulations of the CRBN ligand-binding pocket.
• Construction of free energy landscapes and Markov state models from MD trajectories.
• Analysis of conformational and tautomeric variability of key binding site residues, particularly His378.

Main Results:

• Identified multiple (meta)stable conformational states of the CRBN binding pocket.
• Characterized the dynamic behavior of His378, revealing conformational and tautomeric variability.
• Discovered a previously unrecognized cavity adjacent to the canonical binding site, associated with the dominant C1 conformation of His378.

Conclusions:

• The study reveals critical structural and dynamic insights into the CRBN ligand-binding site.
• A novel cavity offers a promising target for designing CRBN ligands with improved properties.
• These findings facilitate the development of next-generation CRBN binders for enhanced therapeutic potential and selectivity.