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

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.