Mining the CRBN target space redefines rules for molecular glue-induced neosubstrate recognition

The CRL4^CRBN E3 ubiquitin ligase is the target of molecular glue degrader compounds that reprogram ligase specificity to induce the degradation of clinically relevant neosubstrate proteins. Known cereblon (CRBN) neosubstrates share a generalizable β-hairpin G-loop recognition motif that allows for the systematic exploration of the CRBN target space. Computational mining approaches using structure- and surface-based matchmaking algorithms predict more than 1600 CRBN-compatible G-loop proteins across the human proteome, including the newly discovered helical G-loop motif, and identify the noncanonical neosubstrate binding mode of VAV1 that engages CRBN through a molecular surface mimicry mechanism. This work broadens the CRBN target space, redefines rules for neosubstrate recognition, and establishes a platform for the elimination of challenging drug targets by repurposing CRL4^CRBN through next-generation molecular glue degraders.