G3BP2 is a G-loop-independent neosubstrate of CRBN that binds to an unconventional site on the CRBN LON domain, bypassing canonical CULT domain interactions.12
CRBN employs surface mimicry by mimicking an endogenous binding partner of G3BP2's NTF2L domain to hijack a preexisting PPI hotspot, enabling novel neosubstrate recruitment.1
Ligand-induced conformational changes in CRBN create an extended PPI hotspot spanning CULT and LON domains, diversifying target engagement beyond traditional G-loop degrons.1
This binding mode is distinct from other CRBN neosubstrates like VAV1, which uses surface mimicry resembling GSPT1 degron, highlighting diverse recognition mechanisms.12
Structural and computational approaches rationalize G3BP2's engagement, aiding discovery of novel neosubstrate binding modes for molecular glue degraders.1