期刊
NATURE CHEMICAL BIOLOGY
卷 14, 期 7, 页码 706-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41589-018-0055-y
关键词
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资金
- NIH [NCI R01CA214608]
- Harvard University William F. Milton Fund
- Friends of Dana Farber grant
- Claudia Adams Barr Program for Innovative Cancer Research
- Linde Family Foundation
- Damon Runyon Cancer Research foundation [DRG-2196-14]
- National Institute of General Medical Sciences from National Institutes of Health [P41 GM103403]
- NIH-ORIP HEI grant [S10 RR029205]
- DOE Office of Science by Argonne National Laboratory [DE-AC02-06CH11357]
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.
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