Kristin Richling, Promega, USA
Targeted protein degradation is a promising new therapeutic strategy consisting of small molecules, most commonly molecular glues or Proteolysis Targeting Chimeras (PROTACs), which elicit degradation of a target protein. Significant challenges persist to characterize the cellular mechanism of action and the highly dynamic interactions required for degradation. One of the keys steps in the pathway is the formation of an induced ternary complex consisting of the target protein:degrader:E3 ligase component. Here we will present several research stories investigating the role and types of formation of cellular ternary complexes, and how this is correlated with degradation outcome for several different targets and E3 ligase combinations. We will also demonstrate how ternary complex ensemble modeling can predict target lysine positioning and whether mutations to these residues in the cellular environment impacts PROTAC-mediated target ubiquitination. The approaches highlighted will further understanding of cellular mechanism of action and can be used to advance discoveries in the area of targeted protein degradation and induced proximity.
