The transition between active and inactive conformations of Abl kinase studied by rock climbing and Milestoning

ConclusionsThe transition from DFG-in to DFG-out in Abl kinase was simulated using atomic resolution of a fully solvated protein yielding detailed description of the kinetics and the mechanism of the DFG flip. The results are consistent with other computational methods that simulate the kinetics and with some indirect experimental measurements.General significanceThe activation of kinases includes a conformational transition of the DFG motif that is important for enzyme activity but is not accessible to conventional Molecular Dynamics. We propose a detailed mechanism for the transition, at a timescale longer than conventional MD, using a combination of reaction path and Milestoning algorithms. The mechanism includes local structural adjustments near the binding site as well as collective interactions with more remote residues.Graphical abstractChanges in the salt bridge between Lys271 and Glu286 for inactive (a), an intermediate state (B), and active (C) states
Source: Biochimica et Biophysica Acta (BBA) General Subjects - Category: Biochemistry Source Type: research