A number of structural factors modulate the activity of Abelson (Abl) tyrosine kinase, whose deregulation is often related to oncogenic processes. In the activated form of Abl, the modulatory SH2 domain binds the N-lobe of catalytic kinase domain (KD). In this assembly, the SH2 acts as allosteric modulator enhancing the activation loop (A-loop) trans-autophosphorylation, a required step for a full kinase activity. Nevertheless, a detailed explanation of how the SH2 affects the A-loop accessibility is still missing. Here, we coupled classical MD simulations with free energy calculations to clarify a possible mechanism at the basis of such allosteric control. Through comparative analysis, our simulations augment the interpretation of the existing Abl experimental data, revealing a dynamical network of interactions that interconnect SH2 domain-binding with A-loop plasticity and its autophosphorylation in Abl. This signaling network engages the DFG motif and, importantly, other conserved structural elements of the kinase domain, namely the EPK-ELK H-bond network and the HRD motif. Our results show that the signal propagation for modulating the A-loop spatial localization is highly dependent on the HRD motif conformation, which thus acts as the central hub of this (allosteric) signaling network controlling Abl activation and function. Importantly, Thus, these results may help the rational design of new Abl binders that interfere directly or allosterically with this signaling network.

HRD motif as the central hub of the signaling network for activation loop autophosphorylation in Abl kinase

252nd National Meeting (2016)

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