Functional pocketomes and complete allosteric maps of five protein kinases
- 1Wellcome Sanger Institute
Abstract
Protein kinases are central to regulation, dysregulated in many diseases, and the targets of a hundred clinically-approved drugs. Structural conservation of kinase active sites makes the development of selective inhibitors challenging. Targeting allosteric sites can increase selectivity, overcome resistance mutations, and activate kinases. However, most kinases have no known allosteric sites. Moreover, the conservation of allosteric regulation in proteins with the same structural fold is unclear. Here, we address this question by using >390,000 measurements of mutational effects on activity and abundance to construct complete comparative energetic and allosteric maps of five human protein kinase domains: SRC, FGR, JNK2/MAPK9, ZAK/MAP3K20, and TSSK2. For inhibition, all five kinases have distance-dependent allosteric regulation. However allostery is anisotropic, and each protein has a distinct allosteric architecture and surface to therapeutically target. A set of inhibitory allosteric pockets close to the active site is conserved in all five proteins, but more distal allosteric pockets are protein-specific. These include pockets that are activatory in one kinase and inhibitory in another. Differences in allosteric regulation are particularly striking for activation, where the allosteric maps are highly diverged. Our results show that proteins with the same structural fold have different energetic architectures and allosteric pockets. Mapping the 'functional pocketomes' of kinases and other clinically-important targets should empower the development of more selective therapeutics.
Related
- Mapping Functional Transitions across Protein Homologues from a Single Simulation: Application of gEDES-HM to Adenylate Kinases
- From Closed to Mighty: How GTP-Induced Allosteric Dynamics, Dimerization, and Membrane Binding Transform a Bacterial Dynamin-like Protein.
- Intrinsically disordered regions of Src and Abl kinases contribute to membrane binding
- Functional dissection of Drosophila Myc cis-regulatory modules (Myc-CRMs) reveals developmentally active DNA-protein interactions
- A Proximity-Driven Functional Screening Platform for the Discovery of Noninhibitory USP7 Ligand Enabling Targeted Protein Stabilization
BibTeX
@misc{folgado2026functional,
title = {{Functional pocketomes and complete allosteric maps of five protein kinases}},
author = {C. Folgado and A. Beltran and B. Lehner},
howpublished = {bioRxiv},
year = {2026},
month = aug,
doi = {10.64898/2026.08.04.742685},
url = {https://www.biorxiv.org/content/10.64898/2026.08.04.742685v2},
note = {CC BY},
}
RIS
TY - UNPB
TI - Functional pocketomes and complete allosteric maps of five protein kinases
AU - C. Folgado
AU - A. Beltran
AU - B. Lehner
PY - 2026
DA - 2026/08/04
PB - bioRxiv
DO - 10.64898/2026.08.04.742685
UR - https://www.biorxiv.org/content/10.64898/2026.08.04.742685v2
AB - Protein kinases are central to regulation, dysregulated in many diseases, and the targets of a hundred clinically-approved drugs. Structural conservation of kinase active sites makes the development of selective inhibitors challenging. Targeting allosteric sites can increase selectivity, overcome resistance mutations, and activate kinases. However, most kinases have no known allosteric sites. Moreover, the conservation of allosteric regulation in proteins with the same structural fold is unclear. Here, we address this question by using >390,000 measurements of mutational effects on activity and abundance to construct complete comparative energetic and allosteric maps of five human protein kinase domains: SRC, FGR, JNK2/MAPK9, ZAK/MAP3K20, and TSSK2. For inhibition, all five kinases have distance-dependent allosteric regulation. However allostery is anisotropic, and each protein has a distinct allosteric architecture and surface to therapeutically target. A set of inhibitory allosteric pockets close to the active site is conserved in all five proteins, but more distal allosteric pockets are protein-specific. These include pockets that are activatory in one kinase and inhibitory in another. Differences in allosteric regulation are particularly striking for activation, where the allosteric maps are highly diverged. Our results show that proteins with the same structural fold have different energetic architectures and allosteric pockets. Mapping the 'functional pocketomes' of kinases and other clinically-important targets should empower the development of more selective therapeutics.
ER -