Profiling nuclear cysteine ligandability and effects on nuclear localization using proximity labeling-coupled chemoproteomics.

ABSTRACT: The nucleus controls cell growth and division through coordinated interactions between nuclear proteins and chromatin. Mutations that impair nuclear protein association with chromatin are implicated in numerous diseases. Covalent ligands are a promising strategy to pharmacologically target nuclear proteins, such as transcription factors, which lack ordered small-molecule binding pockets. To identify nuclear cysteines that are susceptible to covalent liganding, we couple proximity labeling (PL), using a histone H3.3-TurboID (His-TID) construct, with chemoproteomics. Using covalent scout fragments, KB02 and KB05, we identified ligandable cysteines on proteins involved in spindle assembly, DNA repair, and transcriptional regulation, such as Cys101 of histone acetyltransferase 1 (HAT1). Furthe

SUBMITTER: Peng Q 

PROVIDER: S-EPMC10960692 | biostudies-literature | 2024 Mar

REPOSITORIES: biostudies-literature