2025/06/09 by Zhiheng Deng, Huasong Ai, Qiang Shi +10 · 1 voice
Biochemistry, Genetics and Molecular Biology · #Protein Degradation and Inhibitors #Ubiquitin and proteasome pathways #Histone Deacetylase Inhibitors Research
paper · pdf · doi:10.1101/2025.06.08.658527
openalex created_date 2025/06/09 · openalex publication_date 2025/06/09 · openalex updated_date 2026/07/28
Abstract Immunomodulatory imide drugs (IMiDs) redirect the CUL4–RBX1–DDB1–CRBN (CRL4 CRBN ) ligase to ubiquitylate and degrade disease-linked proteins, but the full picture of how IMiDs glue the neosubstrate within the whole CRL4 CRBN complex remains unknown. We determined cryo-electron microscopy structures of eight approved or clinical IMiDs in full CRL4 CRBN ubiquitylation complexes at resolutions up to 3.4 Å, and revealed how these structurally distinct IMiDs exploit the structural plasticity of CRL4 CRBN to organize conformationally conserved and compact active ubiquitylation assemblies with the neosubstrate IKZF3. Four “next-generation” IMiDs were found to additionally engage a cryptic gluing-driven interfacial (GDI) pocket at the non-degron zinc finger 3 (ZF3) of IKZF3, which contributes to their enhanced efficacy and neosubstrate specificity. The identification of cryptic gluing-driven pockets formed only in full ubiquitylation complexes provides new structure-directed design opportunities for IMiDs to improve therapeutic efficacy.