Thalidomide-inspired immunomodulatory imide drugs (IMiDs) redirect the CUL4–RBX1–DDB1–CRBN (CRL4CRBN) ligase to ubiquitylate and degrade disease-linked proteins. However, the complete mechanistic framework of how thalidomide inspired MGDs (molecular glue degraders) “glue” the neosubstrate within the whole CRL4CRBN ligase complex remains undefined. Here, we report cryo-EM structures of eight approved or clinical-stage IMiDs in fully CRL4CRBN ubiquitylation complexes at resolutions up to 3.4 Å, deciphering how CRL4CRBN catalyzes ubiquitylation of the IMiD-glued neosubstrate, IKZF3. Eight cryo-EM structures reveal a unified and unexpectedly compact architecture of CRL4CRBN–IMiD–IKZF3 ubiquitylation complex. The non-degron zinc finger 3 (ZF3) of IKZF3, previously unresolved in ternary complex structures, is now clearly visualized inserting into a groove adjacent to the IMiD-binding site, where it tethers the CRBN Lon domain, RBX1, and the E2 ubiquitin-conjugating enzyme, thereby contributing to the overall compact and catalytically competent assembly. Strikingly, four next-generation IMiDs are observed to engage a previously unrecognized gluing-driven interfacial (GDI) pocket formed by the IKZF3 ZF3 and CRBN Lon domains, providing a structural basis for their enhanced degradation efficacy and neosubstrate specificity. The discovery of cryptic GDI interactions, formed and observable only in fully ubiquitination complexes, provides critical insights for rational optimization of MGDs therapeutic efficacy.