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

Pelin Ayaz, Agatha Lyczek, YiTing Paung, Victoria R. Mingione, Roxana E. Iacob, Parker W. Waal, John R. Engen, Markus A. Seeliger (), Yibing Shan () and David E. Shaw ()
Additional contact information
Pelin Ayaz: D. E. Shaw Research
Agatha Lyczek: Stony Brook University School of Medicine
YiTing Paung: Stony Brook University School of Medicine
Victoria R. Mingione: Stony Brook University School of Medicine
Roxana E. Iacob: Northeastern University
Parker W. Waal: D. E. Shaw Research
John R. Engen: Northeastern University
Markus A. Seeliger: Stony Brook University School of Medicine
Yibing Shan: D. E. Shaw Research
David E. Shaw: D. E. Shaw Research

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-36956-5

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