Dynamics of Post-Translational Modification Inspires Drug Design in the Kinase Family.

Post-translational modification (PTM) on protein plays important roles in the regulation of cellular function and disease pathogenesis. The systematic analysis of PTM dynamics presents great opportunities to enlarge the target space by PTM allosteric regulation. Here, we presented a framework by integrating the sequence, structural topology, and particular dynamics features to characterize the functional context and druggabilities of PTMs in the well-known kinase family. The machine learning models with these biophysical features could successfully predict PTMs. On the other hand, PTMs were identified to be significantly enriched in the reported allosteric pockets and the allosteric potential of PTM pockets were thus proposed through these biophysical features. In the end, the covalent inhibitor DC-Srci-6668 targeting the PTM pocket in c-Src kinase was identified, which inhibited the phosphorylation and locked c-Src in the inactive state. Our findings represent a crucial step toward PTM-inspired drug design in the kinase family.