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

Author

Listed:
  • 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
    Relay Therapeutics)

  • 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
    Columbia University)

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.

Suggested Citation

  • Pelin Ayaz & Agatha Lyczek & YiTing Paung & Victoria R. Mingione & Roxana E. Iacob & Parker W. Waal & John R. Engen & Markus A. Seeliger & Yibing Shan & David E. Shaw, 2023. "Structural mechanism of a drug-binding process involving a large conformational change of the protein target," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-36956-5
    DOI: 10.1038/s41467-023-36956-5
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    References listed on IDEAS

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    1. Jianming Zhang & Francisco J. Adrián & Wolfgang Jahnke & Sandra W. Cowan-Jacob & Allen G. Li & Roxana E. Iacob & Taebo Sim & John Powers & Christine Dierks & Fangxian Sun & Gui-Rong Guo & Qiang Ding &, 2010. "Targeting Bcr–Abl by combining allosteric with ATP-binding-site inhibitors," Nature, Nature, vol. 463(7280), pages 501-506, January.
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    Cited by:

    1. Wei Lu & Jixian Zhang & Weifeng Huang & Ziqiao Zhang & Xiangyu Jia & Zhenyu Wang & Leilei Shi & Chengtao Li & Peter G. Wolynes & Shuangjia Zheng, 2024. "DynamicBind: predicting ligand-specific protein-ligand complex structure with a deep equivariant generative model," Nature Communications, Nature, vol. 15(1), pages 1-13, December.

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