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0This research introduces a scalable computational and experimental pipeline designed to map the "latent interactome" of the CRL4-CRBN E3 ubiquitin ligase. By combining a high-throughput yeast-based binding assay called GluePCA with an AI-driven surface-mimicry tool named MaSIF-mimicry, the authors identified over 200 new protein interactors that bind to the ligase in the presence of the drug pomalidomide. The study reveals that many proteins not typically degraded by generic drugs still possess druggable interfaces, providing a massive library of starting points for future molecular glue degrader (MGD) development. Structural analysis further demonstrates how accessory domains and tandem zinc fingers contribute to binding specificity and drug-induced degradation. Finally, the authors successfully used this workflow to discover a novel degrader for the RNF39 protein, proving the pipeline's ability to identify actionable therapeutic leads. This integrated approach significantly expands the known target space for proximity-inducing drugs beyond traditional sequence-based motifs.
References:
Galli P, Xiao S, Meng Y, et al. Proteome-wide identification of the druggable CRBN interactome[J]. Nature Biotechnology, 2026: 1-10.
