![]() Crystallographic studies of SCF Tir1-IAA-AID show auxin occupying a pocket located within the TIR1 substrate recognition domain, patching a hole in the degron binding site and completing a hydrophobic surface that drives protein-AID association 7, 8. When auxin is present, ubiquitin ligase SCF Tir1 gains the ability to bind auxin inducible degron (AID) and promote ubiquitination and eventual destruction of the transcription factor by the ubiquitin proteasome system (UPS) 6. A well-studied example of a naturally occurring molecular glue is auxin (indole-3-acetic acid or IAA), a plant hormone that regulates growth and development by orchestrating the degradation of a family of transcription factors through a conserved degron 5. ![]() In particular, molecular glues drive ternary complex formation by providing necessary protein-glue-protein contacts and by promoting new protein-protein contacts 4. These include bispecific recombinant proteins and antibody agents (e.g., BiTEs and DART platforms) that activate innate T-cells to direct their activity toward tumor cells, and molecular glues (i.e., IMiDs, aryl-sulfonamides) that direct the activity of a protein complex toward a neo-substrate 1, 2, 3. Several therapeutic modalities have emerged wherein ternary complex formation is critical to their mechanism of action. Our findings establish a predictive framework to guide the design of potent degraders. Additionally, we develop a ternary-complex structure modeling workflow to calculate the total buried surface area at the interface, which is in agreement with the measured ternary complex binding affinity. Ternary complex binding affinity and cooperativity correlates well with degradation potency and initial rates of degradation. ![]() Ternary-complex attributes and degradation activity parameters are evaluated by varying components of the PROTAC’s architecture. Herein, we characterize PROTAC-mediated ternary complex formation and degradation by employing von Hippel–Lindau protein (VHL) recruiting PROTACs for two different target proteins, SMARCA2 and BRD4. The design of PROTACs is challenging multiple steps involved in PROTAC-induced degradation make it difficult to establish coherent structure-activity relationships. Targeted protein degradation via “hijacking” of the ubiquitin-proteasome system using proteolysis targeting chimeras (PROTACs) has evolved into a novel therapeutic modality. ![]()
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