title: Conformational Selection and Induced Fit Mechanisms in the Binding of an Anticancer Drug to the c-Src Kinase.
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.
authors.affiliation: Structural Biology and Biocomputing Programme, Spanish National Cancer Research Centre (CNIO), c/Melchor Fernandez Almagro 3, 28029, Madrid, Spain.
authors.forename: Maria Agnese
authors.initials: MA
authors.lastname: Morando
authors.affiliation: Institute of Structural and Molecular Biology, University College London, London WC1E 6BT, United Kingdom.|Department of Chemistry, University College London, London WC1E 6BT, United Kingdom.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Saladino
authors.affiliation: Institute of Structural and Molecular Biology, University College London, London WC1E 6BT, United Kingdom.
authors.forename: Nicola
authors.initials: N
authors.lastname: D'Amelio
authors.affiliation: Department of Chemistry, University College London, London WC1E 6BT, United Kingdom.
authors.forename: Encarna
authors.initials: E
authors.lastname: Pucheta-Martinez
authors.affiliation: Department of Chemistry, University College London, London WC1E 6BT, United Kingdom.
authors.forename: Silvia
authors.initials: S
authors.lastname: Lovera
authors.affiliation: Chemistry Department, University of Florence, 50019, Sesto Fiorentino (FI), Italy.
authors.forename: Moreno
authors.initials: M
authors.lastname: Lelli
authors.affiliation: Spectroscopy and NMR Unit, Spanish National Cancer Research Centre (CNIO), c/Melchor Fernandez Almagro 3, 28029, Madrid, Spain.
authors.forename: Blanca
authors.initials: B
authors.lastname: López-Méndez
authors.affiliation: Spectroscopy and NMR Unit, Spanish National Cancer Research Centre (CNIO), c/Melchor Fernandez Almagro 3, 28029, Madrid, Spain.
authors.forename: Marco
authors.initials: M
authors.lastname: Marenchino
authors.affiliation: Spectroscopy and NMR Unit, Spanish National Cancer Research Centre (CNIO), c/Melchor Fernandez Almagro 3, 28029, Madrid, Spain.
authors.forename: Ramón
authors.initials: R
authors.lastname: Campos-Olivas
authors.affiliation: Institute of Structural and Molecular Biology, University College London, London WC1E 6BT, United Kingdom.|Department of Chemistry, University College London, London WC1E 6BT, United Kingdom.
authors.forename: Francesco Luigi
authors.initials: FL
authors.lastname: Gervasio
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry*; D000081247:CSK Tyrosine-Protein Kinase; D000068877:Imatinib Mesylate / Q000737:chemistry*; D008024:Ligands; D008279:Magnetic Resonance Imaging; D008968:Molecular Conformation; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D020349:Surface Plasmon Resonance; D019061:src-Family Kinases / Q000737:chemistry*
chemical_list: D000970:Antineoplastic Agents; D008024:Ligands; D000068877:Imatinib Mesylate; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases