Please use this identifier to cite or link to this item:http://hdl.handle.net/20.500.12105/8571
Title
Conformational Selection and Induced Fit Mechanisms in the Binding of an Anticancer Drug to the c-Src Kinase
Author(s)
Date issued
2016-04-18
Citation
Sci Rep. 2016;6:24439.
Language
Inglés
Document type
journal article
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.
MESH
Antineoplastic Agents | Imatinib Mesylate | Ligands | Magnetic Resonance Imaging | Molecular Conformation | Molecular Dynamics Simulation | Protein Binding | Surface Plasmon Resonance | src-Family Kinases
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DOI
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