9gy3
Crystal structure of CRBNmidi in complex with (S)-dHTC1
Structural highlights
DiseaseCRBN_HUMAN Autosomal recessive nonsyndromic intellectual deficit;Distal monosomy 3p. The disease is caused by mutations affecting the gene represented in this entry. FunctionCRBN_HUMAN Component of some DCX (DDB1-CUL4-X-box) E3 protein ligase complex, a complex that mediates the ubiquitination and subsequent proteasomal degradation of target proteins and is required for limb outgrowth and expression of the fibroblast growth factor FGF8. In the complex, may act as a substrate receptor. Regulates the assembly and neuronal surface expression of large-conductance calcium-activated potassium channels in brain regions involved in memory and learning via its interaction with KCNT1.[1] [2] Publication Abstract from PubMedChemical inducers of proximity (CIPs) stabilize biomolecular interactions, often causing an emergent rewiring of cellular biochemistry. While rational design strategies can expedite the discovery of heterobifunctional CIPs, monovalent, molecular glue-like CIPs have relied predominantly on serendipity. Envisioning a prospective approach to discover molecular glues for a pre-selected target, we hypothesized that pre-existing ligands could be systematically decorated with chemical modifications to empirically discover protein-ligand surfaces that are tuned to cooperatively engage another protein interface. Here, we used sulfur(VI)-fluoride exchange (SuFEx)-based high-throughput chemistry (HTC) to install 3,163 structurally diverse chemical building blocks onto ENL and BRD4 ligands and then screened the crude products for degrader activity. This revealed dHTC1, a potent, selective, and stereochemistry-dependent degrader of ENL. It recruits CRL4 (CRBN) to ENL through an extended interface of protein-protein and protein-ligand contacts, but only after pre-forming the ENL:dHTC1 complex. We also characterized two structurally distinct BRD4 degraders, including dHTC3, a molecular glue that selectively dimerizes the first bromodomain of BRD4 to SCF (FBXO3) , an E3 ligase not previously accessible for chemical rewiring. Altogether, this study introduces HTC as a facile tool to discover new CIPs and actionable cellular effectors of proximity pharmacology. High-throughput diversification of protein-ligand surfaces to discover chemical inducers of proximity.,Shaum JB, Munoz I Ordono M, Steen EA, Wenge DV, Cheong H, Hunkeler M, Bilotta EM, Rutter Z, Barta PA, Thornhill AM, Milosevich N, Hargis LM, Janowski J, Bishop TR, Carter TR, da Camara B, Hinterndorfer M, Dada L, He WJ, Offensperger F, Furihata H, Schweber SR, Hatton C, Wen Y, Cravatt BF, Engle KM, Donovan KA, Melillo B, Kitamura S, Ciulli A, Armstrong SA, Fischer ES, Winter GE, Erb MA bioRxiv [Preprint]. 2025 Sep 4:2024.09.30.615685. doi: 10.1101/2024.09.30.615685. PMID:40950085[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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