Functional pocketomes and complete allosteric maps of five protein kinases

Across five human kinase domains (SRC, FGR, JNK2/MAPK9, ZAK/MAP3K20, and TSSK2), >390,000 mutational-effect measurements reveal distance-dependent allosteric regulation with conserved near-active-site pockets.

• Why it matters: Selective kinase inhibition is hard because active sites are structurally conserved, and most kinases lack known allosteric sites. The study tests whether allosteric regulation is conserved across proteins sharing a fold.
• What they did: They used >390,000 measurements of mutational effects on activity and abundance to build complete comparative energetic and allosteric maps for the five kinase domains. They then compared pocket locations and whether they modulate activity or abundance.
• The result: All five show inhibitory allostery, but it is anisotropic with distinct architectures: near pockets are conserved, while more distal pockets are protein-specific and can switch between activatory and inhibitory effects. This enables “functional pocketome” mapping to guide more selective therapeutic development.

AI summary of the abstract · may contain errors · not medical advice · read the paper.