Molecular Insights on the Conformational Transitions and Activity Regulation of the c-Met Kinase Induced by Ligand Binding

Abstract

The tyrosine-protein kinase Met (c-Met) is an important signaling molecule involved in cellular growth and division. The dysregulation of c-Met may induce many fatal diseases, including non-small cell lung cancer, gastrointestinal cancers, hepatocellular carcinoma, etc. The activation of the c-Met kinase is dominant by the structure and dynamics of many important functional motifs, which are regulated by adenosine triphosphate (ATP) binding. c-Met inhibitors bind to the ATP-binding site or the allosteric pocket to compete with ATP molecules or alter the conformation of the function-related domains. Nevertheless, the mechanisms of ligand binding to c-Met are still unclear, especially the regulation of the functional motifs by different inhibitors. These greatly impede the development of novel drugs to overcome the drug tolerance to the currently marketed c-Met inhibitors. In this study, we used enhanced sampling technology to study the binding and regulation of two specific c-Met inhibitors. The results show that the two ligands adopt different binding processes even though with similar binding affinity. More importantly, our results uncovered different protein conformational features and the correlated motions of functional motifs regulated by the inhibitors, providing the structural basis for the functional suppression of the protein kinases.