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Sci Rep. 2016 Apr 18;6:24439. doi: 10.1038/srep24439.

Conformational Selection and Induced Fit Mechanisms in the Binding of an Anticancer Drug to the c-Src Kinase.

Author information

1
Structural Biology and Biocomputing Programme, Spanish National Cancer Research Centre (CNIO), c/Melchor Fernandez Almagro 3, 28029, Madrid, Spain.
2
Institute of Structural and Molecular Biology, University College London, London WC1E 6BT, United Kingdom.
3
Department of Chemistry, University College London, London WC1E 6BT, United Kingdom.
4
Chemistry Department, University of Florence, 50019, Sesto Fiorentino (FI), Italy.
5
Spectroscopy and NMR Unit, Spanish National Cancer Research Centre (CNIO), c/Melchor Fernandez Almagro 3, 28029, Madrid, Spain.

Abstract

Understanding the conformational changes associated with the binding of small ligands to their biological targets is a fascinating and meaningful question in chemistry, biology and drug discovery. One of the most studied and important is the so-called "DFG-flip" of tyrosine kinases. The conserved three amino-acid DFG motif undergoes an "in to out" movement resulting in a particular inactive conformation to which "type II" kinase inhibitors, such as the anti-cancer drug Imatinib, bind. Despite many studies, the details of this prototypical conformational change are still debated. Here we combine various NMR experiments and surface plasmon resonance with enhanced sampling molecular dynamics simulations to shed light into the conformational dynamics associated with the binding of Imatinib to the proto-oncogene c-Src. We find that both conformational selection and induced fit play a role in the binding mechanism, reconciling opposing views held in the literature. Moreover, an external binding pose and local unfolding (cracking) of the aG helix are observed.

PMID:
27087366
PMCID:
PMC4834493
DOI:
10.1038/srep24439
[Indexed for MEDLINE]
Free PMC Article

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