Global profiling of arginine reactivity and ligandability

ABSTRACT: Despite the crucial biological roles of arginine, its reactivity and ligandability in the human proteome are not well-explored. In this study, we employed the activity-based protein profiling approach using phenylglyoxal-based chemical probes to globally profile arginine residues. By screening a focused library of 13 phenylglyoxal derivatives, we identified probes that offered enhanced coverage and selectivity. This led to the quantification of 4,606 arginine sites across various human cell lines. We also assessed arginine reactivity through on-beads reductive dimethylation quantitative proteomics, which highlighted a subset of hyper-reactive arginines. Competitive fragment screening via DIA-ABPP pinpointed ligandable arginines that influence protein activities, unveiling potential targets for drug discovery. We further mapped these ligandable arginines to specific protein interfaces undergoing significant changes in solvent accessible surface area after protein-protein interactions. These mappings suggested that ligandable arginines could disrupt protein-protein interactions, a hypothesis we validated through co-immunoprecipitation experiments. This study provides a comprehensive overview of arginine reactivity and introduces new insights into the functional and ligandable landscape of the human proteome, underscoring significant therapeutic potentials.

ORGANISM(S): Homo Sapiens

SUBMITTER: Gang Li  

PROVIDER: PXD056202 | iProX | Sat Aug 16 00:00:00 BST 2025

REPOSITORIES: iProX