Structural Basis of Conformational Dynamics in the PROTAC‐Induced Protein Degradation

Abstract Pronounced conformational dynamics is unveiled upon analyzing multiple crystal structures of the same proteins recruited to the same E3 ligases by PROTACs, and yet, is largely permissive for targeted protein degradation due to the intrinsic mobility of E3 assemblies creating a large ubiquitylation zone. Mathematical modelling of ternary dynamics on ubiquitylation probability confirms the experimental finding that ternary complex rigidification need not correlate with enhanced protein degradation. Salt bridges are found to prevail in the PROTAC‐induced ternary complexes, and may contribute to a positive cooperativity and prolonged half‐life. The analysis highlights the importance of presenting lysines close to the active site of the E2 enzyme while constraining ternary dynamics in PROTAC design to achieve high degradation efficiency.