Plasticity in binding confers selectivity in ligand induced protein degradation

By R. Nowak, S. DeAngelo, Dennis L. Buckley, Zhixiang He, K. Donovan, Jian An, N. Safaee, Mark P. Jedrychowski, Charles M. Ponthier, M. Ishoey and 5 more. 2018

492 citations recorded by the source corpus.

Heterobifunctional small-molecule degraders that induce protein degradation through ligase-mediated ubiquitination have shown considerable promise as a new pharmacological modality. However, we currently lack a detailed understanding of the molecular basis for target recruitment and selectivity, which is critically required to enable rational design of degraders. Here we utilize a comprehensive characterization of the ligand-dependent CRBN–BRD4 interaction to demonstrate that binding between proteins that have not evolved to interact is plastic. Multiple X-ray crystal structures show that plasticity results in several distinct low-energy binding conformations that are selectively bound by ligands. We demonstrate that computational protein–protein docking can reveal the underlying interprotein contacts and inform the design of a BRD4 selective degrader that can discriminate between highly homologous BET bromodomains. Our findings that plastic interprotein contacts confer selectivity for ligand-induced protein dimerization provide a conceptual framework for the development of heterobifunctional ligands.Selectivity of ligand-induced protein degradation and dimerization is conferred by plastic interprotein contacts. Computational protein–protein docking reveals the underlying interprotein contacts to inform the design of a BRD4 selective degrader.

Subfields: Molecular Biology, Software

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Citations in the corpus

Modeling the CRL4A ligase complex to predict target protein ubiquitination induced by cereblon-recruiting PROTACs (2022, background): “…be further classi ﬁ ed into three groups based on the relative Model CRL4A complex to predict PROTAC-induced ubiquitination positions of CRBN and E2: (1) “ ring-forming CRL4A ligase complexes, ” with a potential interface ( ≤ 4 Å distance) between CRBN and E2 (conformations 1, 2, 4, 5, and 9; Fig.”
RCSB Protein Data Bank: Enabling biomedical research and drug discovery (2019, background): “103 These proof-of-concept structures open the door-to-structure-guided discovery of similar degraders selective for other protein targets, via engineering of linkers based on structures of specific ligands bound to each of the partners.”
Proteolysis Targeting Chimeras as Therapeutics and Tools for Biological Discovery (2020, unknown): “As we come to understand this new technology better, it is clear that protein-protein contacts between the neo-substrate and E3 complex are a crucial determinant of PROTAC success, as shown in Figure 2 (Bondeson et al., 2018; Gadd et al., 2017; Nowak et al., 2018; Smith et al., 2019; Zorba et al., 2”
PROteolysis TArgeting Chimeras (PROTACs) - Past, Present and Future (2019, methodology): “In a recent study, ternary complex conformation was found to be PROTAC linker-dependent for CRBN and BRD4 [67].”
Acute pharmacological degradation of Helios destabilizes regulatory T cells (2021, unknown): “Cells stably expressing the BRD4 BD2 -GFP with mCherry reporter 19 were seeded at 30–50% confluency in 384-well plates with 50 μL FluoroBrite DMEM media (Thermo Fisher Scientific A18967) containing 10% FBS per well a day before compound treatment.”