2025/10/12 by Ah‐Ram Kim, Kerui Huang, Jared L. Johnson +5 · 1 voice
Biochemistry, Genetics and Molecular Biology · Neuroscience · #Genetic and Kidney Cyst Diseases #Cerebrospinal fluid and hydrocephalus #Microtubule and mitosis dynamics
paper · pdf · doi:10.1101/2025.10.10.681672
Abstract Protein kinases orchestrate cellular processes through phosphorylation, yet the structural basis for their specific binding partner interactions remains largely unmapped. Here, we present a structure-guided atlas of the human and Drosophila kinome, built by applying a new interface-aware scoring framework (iLIS) to AlphaFold-Multimer predictions. The resulting atlas recapitulates hallmark sequence preferences, confirms previously reported and functionally related protein-protein interactions, and uncovers unrecognized docking interactions. Notably, our analysis predicts a potentially widespread docking motif on homeodomain transcription factors that mediates interactions with basophilic kinases. Furthermore, we map putative allosteric interaction hotspots across the kinome and provide proof-of-concept evidence that targeting these surfaces can inhibit kinase activity. Finally, we demonstrate the physiological utility of the atlas by identifying a novel regulatory mechanism between Sgg/GSK3 and Hnf4 that controls lipid metabolism in vivo . This resource provides a blueprint for dissecting signaling networks and for the rational design of docking-site-specific kinase modulators.