Activity-based protein profiling (ABPP) using oxaziridine probes for Redox-Activated Chemical Tagging (ReACT) identifies new hyperreactive, ligandable methionine sites on CDK4. (a) Structures of Ox1-alkyne, Ox32-alkyne, and Ox1-azide ABPP probes. (b) Ribbon diagram of CDK4 (PDB: 2W9Z). Methionine residues modified by oxaziridines are highlighted, with colored squares representing the corresponding ReACT reagents found to modify each site. Each residue is additionally labeled with its calculated solvent accessibility. (c) Shotgun proteomics general workflow. Isolated protein is first incubated with compound. After excess compound is neutralized, protein is tryptic-digested and analyzed via MS/MS to reveal compound site(s) of modification.