Conformational dynamics in insulin receptor kinase reveal a type III allosteric pocket.

ABSTRACT: Allosteric modulation is a promising strategy for selective kinase inhibition, yet structural insights into allosteric pockets remain limited across the human kinome. In this work, we present comprehensive characterization of a type III allosteric pocket in the insulin receptor kinase (IRK), integrating structural, conformational, and thermodynamic analyses. Specifically, we used microsecond-scale atomistic molecular dynamics simulations in combination with alchemical free energy calculations to investigate apo and inhibitor-bound IRK structures. Our findings indicate that the type III pocket is a "back pocket" in IRK, sandwiched between the N- and C-terminal lobes. It features a hydrophobic cleft of aliphatic and aromatic non-polar residues with a charge center for electrostatic interacti

SUBMITTER: Verma J 

PROVIDER: S-EPMC12817300 | biostudies-literature | 2026 Feb

REPOSITORIES: biostudies-literature