Energetic dissection of Gleevec's selectivity toward human tyrosine kinases

Abstract

Protein kinases are obvious drug targets against cancer due to their central role in cellular regulation. Since the discovery of Gleevec, a potent and specific inhibitor of Abl kinase, as a highly successful cancer therapeutic, the ability of this drug to distinguish between Abl and other tyrosine kinases like Src has been intensely investigated, but without much success. Using NMR and fast kinetics, we establish a novel model that solves this longstanding question of two tyrosine kinases adopting almost identical structures when bound to Gleevec, yet having vastly different affinities. In contrast to all other proposed models we show that the origin of Abl’s high affinity lies predominantly in a conformational change after binding. An energy landscape that provides tight affinity via an induced-fit and binding plasticity via conformational selection mechanism is likely to be general for many inhibitors.

Molecular Dynamics Simulations and Structural Network Analysis of c-Abl and c-Src Kinase Core Proteins: Capturing Allosteric Mechanisms and Communication Pathways from Residue Centrality

“…Computational approaches have studied the atomic details of the protein kinase dynamics and regulation at different levels of complexity : from detailed analyses of the catalytic domain and drug resistance [51][52][53][54][55][56][57][58][59] to simulations of the regulatory assemblies [60][61][62][63][64] . In our previous studies, we analyzed mechanisms of allosteric kinase regulation by integrating multiscale simulations and modeling of long-range communications 60,61 .…”

NMR line shape analysis of a multi-state ligand binding mechanism in chitosanase

“…A similar conformational change was also reported in a family GH19 chitinase from rye seeds (Ohnuma et al 2013), indicating a close relationship between the mechanisms of GH46 and GH19 enzymes . Ligand interactions coupled to conformational changes in protein structures may be sensitively resolved using nuclear magnetic resonance (NMR) line shape analysis (Agafonov et al 2014;Günther and Schaffhausen 2002;Kaplan and Fraenkel 1980;Kern et al 1995;Mittag et al 2006Mittag et al , 2003Rao 1989). In this report we analyzed NMR line shapes in titrations of CsnN174 chitosanase with substrate and product molecules to illuminate the mechanism of coupling between ligand binding and the conformational change in the protein structure.…”

Conformational landscape and low lying excited states of imatinib

“…Due to its high flexibility, IMT is expected to adapt easily to different environments. Moreover, as pointed out by Agafonov et al [49], not only the drug, but the protein itself undergoes structural changes during and after binding. For this reason, besides the conformational landscape, another interest was to compare the 3D structure of the bioactive conformations found in different IMT-tyrosine kinases complexes [9,10,18,23] to that of other possible conformers.…”