Cereblon induces G3BP2 neosubstrate degradation using molecular surface mimicry

Area of Science:

• Biochemistry
• Molecular Biology
• Drug Discovery

Background:

• Molecular glue degraders (MGDs) are a therapeutic modality that hijacks E3 ubiquitin ligases to degrade target proteins.
• Effective MGDs typically bind cereblon (CRBN) and recruit neosubstrates via molecular mimicry of natural degrons.
• CRBN is a substrate receptor for the Cullin 4-RING E3 ubiquitin ligase complex (CRL4^CRBN).

Purpose of the Study:

• To identify novel neosubstrates and characterize their interaction with CRBN.
• To elucidate the mechanism by which MGDs can target proteins through unconventional binding sites.
• To explore new strategies for expanding the target repertoire of MGDs.

Main Methods:

• Biochemical assays to characterize protein-protein interactions.
• Structural biology techniques to determine the ternary complex structure.
• Cellular assays to validate target engagement and degradation.

Main Results:

• Identification of G3BP2 (Ras-GAP SH3 domain-binding protein 2) as a novel CRBN neosubstrate.
• G3BP2 interacts with CRBN through an unconventional binding site on the CRBN LON domain, distinct from canonical degron interactions.
• The CRBN-G3BP2 interaction mimics a known protein-protein interaction (PPI) of G3BP2, stabilizing a composite neosurface.
• This interaction bypasses the need for mimicking a natural CRBN degron.

Conclusions:

• CRBN can engage neosubstrates via non-canonical binding sites, expanding the scope of MGDs.
• Mimicking existing protein-protein interaction hotspots ('glueprints') is a viable strategy for designing novel MGDs.
• This approach offers a rational framework for expanding the MGD target repertoire to previously inaccessible proteins.