Lenalidomide Stabilizes Protein-Protein Complexes by Turning Labile Intermolecular H-Bonds into Robust Interactions

Area of Science:

• Biochemistry
• Molecular Biology
• Drug Discovery

Background:

• Targeted protein degradation is a key therapeutic strategy, exemplified by anti-myeloma drugs like lenalidomide.
• These drugs leverage the E3 ligase Cereblon (CRBN) to degrade specific client proteins (neo-substrates).
• The high efficiency of ternary complex formation, despite known structures, remains unexplained.

Purpose of the Study:

• To elucidate the molecular mechanisms behind the efficient stabilization of CRBN-neo-substrate complexes by drugs like lenalidomide.
• To investigate the role of intermolecular interactions in the stability of these drug-induced complexes.
• To establish a quantitative link between hydrogen bond characteristics and binding affinities.

Main Methods:

• Structural analysis of CRBN-lenalidomide-CK1α complexes.
• Biophysical techniques to assess binding affinities and hydrogen bond robustness.
• Computational modeling to understand hydrophobic shielding effects.

Main Results:

• Lenalidomide stabilizes the CRBN-CK1α complex primarily through hydrophobic shielding of intermolecular hydrogen bonds.
• A quantitative correlation was identified between the robustness of hydrogen bonds and the binding affinities of the ternary complexes.
• These findings provide insights into the cooperativity effects driving complex formation.

Conclusions:

• Hydrophobic shielding is a critical factor in the high efficiency of drug-induced ternary complex formation.
• Understanding hydrogen bond dynamics can guide the development of novel molecular glues.
• This research facilitates the design of more potent and selective protein degraders for therapeutic applications.