Investigating Protein Degradability through Site-Specific Ubiquitin Ligase Recruitment.

ABSTRACT: We report targeted protein degradation through the site-specific recruitment of native ubiquitin ligases to a protein of interest via conjugation of E3 ligase ligands. Direct comparison of degradation ability of proteins displaying the corresponding bioconjugation handle at different regions of protein surfaces was explored. We demonstrate the benefit of proximal lysine residues and investigate flexibility in linker length for the design of optimal degraders. Two proteins without known small molecule ligands, EGFP and DUSP6, were differentially degraded when modified at different locations on their protein surfaces. Further, the cereblon-mediated degradation of the known PROTAC target ERRα was improved through the recruitment of the E3 ligase to regions different from the known ligand bind

SUBMITTER: Shade O 

PROVIDER: S-EPMC11601344 | biostudies-literature | 2024 Nov

REPOSITORIES: biostudies-literature