biostudies-literaturePeng QNational Institutes of HealthNIGMS NIH HHSNIGMS550-564.e9https://www.ebi.ac.uk/biostudies/studies/S-EPMC10960692biostudies-literatureUnknown31(3)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). FurtheCell chemical biologyProfiling nuclear cysteine ligandability and effects on nuclear localization using proximity labeling-coupled chemoproteomics.PMC10960692R35 GM134964R35GM134964Weerapana EPeng QfalseProfiling nuclear cysteine ligandability and effects on nuclear localization using proximity labeling-coupled chemoproteomics.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). Furthe2024-01-01T00:00:00Z2024 Mar2026-06-01T22:54:18.463Z2025-04-06T10:46:48.133ZS-EPMC109606923808636910.1016/j.chembiol.2023.11.010