Structural mechanism of a drug-binding process involving a large conformational change of the protein target

Atomic-level descriptions of protein-small molecule binding processes that involve a large conformational change of the protein have been elusive. Here, the authors report unguided molecular dynamics simulations of such a process-Abl kinase binding the cancer drug imatinib. Proteins often undergo large conformational changes when binding small molecules, but atomic-level descriptions of such events have been elusive. Here, we report unguided molecular dynamics simulations of Abl kinase binding to the cancer drug imatinib. In the simulations, imatinib first selectively engages Abl kinase in its autoinhibitory conformation. Consistent with inferences drawn from previous experimental studies, imatinib then induces a large conformational change of the protein to reach a bound complex that closely resembles published crystal structures. Moreover, the simulations reveal a surprising local structural instability in the C-terminal lobe of Abl kinase during binding. The unstable region includes a number of residues that, when mutated, confer imatinib resistance by an unknown mechanism. Based on the simulations, NMR spectra, hydrogen-deuterium exchange measurements, and thermostability measurements and estimates, we suggest that these mutations confer imatinib resistance by exacerbating structural instability in the C-terminal lobe, rendering the imatinib-bound state energetically unfavorable.

Automated summary

The authors used molecular dynamics simulations to study the binding process of Abl kinase with the cancer drug imatinib. The simulations revealed that imatinib induces a large conformational change of the protein and identified a region in Abl kinase that is structurally unstable during binding. Mutations in this region confer imatinib resistance by exacerbating structural instability.