Moebitz, Henrik (2015) The ABC of protein kinase conformations. Biochimica et Biophysica Acta Proteins and Proteomics.

Abstract

Conformation plays a crucial role in kinase biology. In this paper, we present a ternary classification scheme of the structural kinome based on the conformation of the DFG-motif (DFG-F and DFG-G side chain torsion) and the displacement of aC-helix and DFG, revealing a small set of major conformations. The DFG-motif occurs in three eclipsed conformations which differ in propensity for aC-helix displacement. The tight interaction between aC-helix and DFG forms a strong bias towards the active conformation and organizes the universal features of active kinases. The activating effect of sequence, phosphorylation, cyclin and inhibitor binding can be estimated by thermodynamic analyses. A likely path for the DFG-out transition, rotation around the bond between DFG-1 and DFG-F after a backbone flip, is suggested by its population in the pdb. Consistent with this mechanism, flexible, lipophilic residues in the path of the DFG-F sidechain and flexibility of aC-helix are required for the transition. Displacement of aC-helix involves subtle shifts in improper torsion angles which propagate to a bending of the C-terminal loop between aC-helix and the HPN motif.

Item Type:	Article
Keywords:	Classification Structural kinome Conformational bias Active conformation Kinase nomenclature
Date Deposited:	13 Oct 2015 13:16
Last Modified:	13 Oct 2015 13:16
URI:	https://oak.novartis.com/id/eprint/3357