Journal
JOURNAL OF CHEMICAL INFORMATION AND MODELING
Volume 61, Issue 3, Pages 1368-1382Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jcim.0c01451
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Funding
- National Science Foundation [ACI-1548562, CHE-1836950, DBI-1950697, MCB130049]
- National Institute of General Medical Sciences [R01GM123336]
- NIH/NCI Cancer Center Support Grant [P30CA006927]
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PROTACs are molecules that induce target protein degradation by combining a target-binding warhead with an E3 ligase-recruiting moiety. A structure-based computational method has been developed to evaluate the suitability of linkers for ternary complex formation, which can explain PROTACs' activity and selectivity. Modeling ternary complex formation can help interpret PROTAC activity and reveal different binding modes within structurally conserved protein families.
Proteolysis-targeting chimaeras (PROTACs) are molecules that combine a target-binding warhead with an E3 ligase-recruiting moiety; by drawing the target protein into a ternary complex with the E3 ligase, PROTACs induce target protein degradation. While PROTACs hold exciting potential as chemical probes and as therapeutic agents, development of a PROTAC typically requires synthesis of numerous analogs to thoroughly explore variations on the chemical linker; without extensive trial and error, it is unclear how to link the two protein-recruiting moieties to promote formation of a productive ternary complex. Here, we describe a structure-based computational method for evaluating the suitability of a given linker for ternary complex formation. Our method uses Rosetta to dock the protein components and then builds the PROTAC from its component fragments into each binding mode; complete models of the ternary complex are then refined. We apply this approach to retrospectively evaluate multiple PROTACs from the literature, spanning diverse target proteins. We find that modeling ternary complex formation is sufficient to explain both activity and selectivity reported for these PROTACs, implying that other cellular factors are not key determinants of activity in these cases. We further find that interpreting PROTAC activity is best approached using an ensemble of structures of the ternary complex rather than a single static conformation and that members of a structurally conserved protein family can be recruited by the same PROTAC through vastly different binding modes. To encourage adoption of these methods and promote further analyses, we disseminate both the computational methods and the models of ternary complexes.
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