Elastic network model of allosteric regulation in protein kinase PDK1

It is shown here that the allosteric effects of the agonist binding to the small lobe upon the activation loop in the large lobe of PDK1 are explainable within a simple 'ball and spring' elastic network model (ENM) of protein dynamics. In particular, the model shows that the bound phospho peptide mimetic fluctuations have a high degree of correlation with the activation loop of PDK1.The ENM approach to small molecule activation of proteins may offer a first pass predictive methodology where affinity is encoded in residues remote from the active site, and aid in the design of specific protein agonists that enhance the allosteric coupling and antagonist that repress it.Phosphorylation dependent protein interactions are a common feature of biological processes [1]. A relevant kinase attaches a phosphate group to a specific tyrosine, threonine or serine residue on the protein surface resulting in a considerable increase in the binding affinity for a target protein. The binding event triggers a conformational change whereby the target protein switches from inactive to active state or vice versa [2]. It is not possible to generalise the nature of the conformational change and it is only with crystallisation that light has been thrown on the mechanism. PDK1 in common with other AGC kinases have a catalytic domain consisting of an N-terminal small lobe harbouring a PDK1-interacting fragment (PIF) binding pocket, a large C-terminal lobe with an activation loop and an ATP binding site in the cleft between the two lobes [3]. The PDK1 kinase is activated by a phosphorylated peptide binding to the PIF pocket [4]. This binding triggers not only local conformational changes in the pocket and the ATP binding site, but also in the remote activation loop. Structural insight into the mechanism of activation of PDK1 has been gained by the crystallisation in the first instance of the inactive version of the protein [5] where the activation loop appears unstructured. And the recent devel