The ABC of protein kinase conformations

Abstract

Due to their involvement in human diseases, protein kinases are an important therapeutic target class. Conformation is a key concept for understanding how functional activity, inhibition and sequence are linked. We assemble and annotate the mammalian structural kinome from the Protein Data Bank on the basis of a universal residue nomenclature. We identify a torsion angle around the Gly of the DFG-motif whose sharp distribution profile corresponds to three eclipsed conformations. This allows the definition a small set of clusters whose distribution shows a bias for the active conformation. A common rationale links the active and inactive state: stabilization of the active conformation, as well as inactivation by displacement of helix-αC or the DFG-motif is governed by the interaction between helix-αC and the DFG motif. In particular, the conformation of the DFG-motif is tightly correlated with the propensity of helix-αC displacement. Our analysis reveals detailed mechanisms for the displacement of helix-αC and the DFG and improves our understanding of the role of individual residues. By pooling conformations from the whole structural kinome, the energetic contributions of sequence and extrinsic factors can be estimated in free energy analyses. This article is part of a Special Issue entitled: Inhibitors of Protein Kinases.

Keywords: Active, αC-out/DFG-out conformation; Classification; Kinase inhibitor; Protein kinase; Universal kinase residue nomenclature.