Insights from protein frustration analysis of BRD4-cereblon degrader ternary complexes show separation of strong from weak degraders.

ABSTRACT: PROteolysis TArgeting Chimeras (PROTACs), also known as ligand-directed degraders (LDDs), are an innovative class of small molecules that leverage the ubiquitin-proteasome system to induce the degradation of target proteins. Structure based design methods are not readily applicable for designing LDDs due to the dynamic nature of the ternary complexes. This study investigates the dynamic properties of five LDD-mediated BRD4-cereblon complexes, focusing on the challenges of evaluating linker efficiency due to the difficulty in identifying suitable computational metrics that correlate well with the cooperativity or degradation propensity of LDDs. We uncovered that protein frustration, a concept originally developed to understand protein folding, calculated for the residues in the protein-prot

SUBMITTER: Yang T 

PROVIDER: S-EPMC11851170 | biostudies-literature | 2025 Feb

REPOSITORIES: biostudies-literature