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dc.contributor.author | Morando, Maria Agnese | |
dc.contributor.author | Saladino, Giorgio | |
dc.contributor.author | D'Amelio, Nicola | |
dc.contributor.author | Pucheta-Martinez, Encarna | |
dc.contributor.author | Lovera, Silvia | |
dc.contributor.author | Lelli, Moreno | |
dc.contributor.author | López-Méndez, Blanca | |
dc.contributor.author | Marenchino, Marco | |
dc.contributor.author | Campos Olivas, Ramon | |
dc.contributor.author | Gervasio, Francesco Luigi | |
dc.date.accessioned | 2019-11-11T11:14:51Z | |
dc.date.available | 2019-11-11T11:14:51Z | |
dc.date.issued | 2016-04-18 | |
dc.identifier.citation | Sci Rep. 2016;6:24439. | es_ES |
dc.identifier.issn | 2045-2322 | es_ES |
dc.identifier.uri | http://hdl.handle.net/20.500.12105/8571 | |
dc.description.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. | es_ES |
dc.description.sponsorship | We acknowledge the EPSRC, grant [EP/M013898/1] for supporting F.L.G. and G.S., the Comunidad Autonoma de Madrid S2010-BMD-2457 (BIPEDD2) for supporting M.A.M. and R.C.-O.'s Unit, the Ministerio de Educacion and UCL for a PhD fellowship to S.L. PRACE Research Infrastructure resources (SuperMUC, MareNostrum, Curie and Hornet), the e-Infrastructure South (Emerald) and HecBioSim (supported by EPSRC, grant no. EP/L000253/1) for the computational resources. We also acknowledge the MRC Biomedical NMR Center of London for generous NMR time allocation. Access to Research Infrastructures activity in the 7th Framework Programme of the EC (Project number: 261863, Bio-NMR) is acknowledged for financial support to conduct the NMR experiments. | es_ES |
dc.language.iso | eng | es_ES |
dc.publisher | Nature Publishing Group | es_ES |
dc.type.hasVersion | VoR | es_ES |
dc.rights.uri | http://creativecommons.org/licenses/by-nc-sa/4.0/ | * |
dc.subject.mesh | Antineoplastic Agents | es_ES |
dc.subject.mesh | Imatinib Mesylate | es_ES |
dc.subject.mesh | Ligands | es_ES |
dc.subject.mesh | Magnetic Resonance Imaging | es_ES |
dc.subject.mesh | Molecular Conformation | es_ES |
dc.subject.mesh | Molecular Dynamics Simulation | es_ES |
dc.subject.mesh | Protein Binding | es_ES |
dc.subject.mesh | Surface Plasmon Resonance | es_ES |
dc.subject.mesh | src-Family Kinases | es_ES |
dc.title | Conformational Selection and Induced Fit Mechanisms in the Binding of an Anticancer Drug to the c-Src Kinase | es_ES |
dc.type | journal article | es_ES |
dc.rights.license | Atribución-NoComercial-CompartirIgual 4.0 Internacional | * |
dc.identifier.pubmedID | 27087366 | es_ES |
dc.format.volume | 6 | es_ES |
dc.format.number | 1 | es_ES |
dc.format.page | 24439 | es_ES |
dc.identifier.doi | 10.1038/srep24439 | es_ES |
dc.contributor.funder | Engineering and Physical Sciences Research Council (Reino Unido) | |
dc.contributor.funder | Comunidad de Madrid (España) | |
dc.contributor.funder | European Commission Joint Research Centre European Community (EC) | |
dc.contributor.funder | Medical Research Council (Reino Unido) | |
dc.contributor.funder | The Francis Crick Institute | |
dc.description.peerreviewed | Sí | es_ES |
dc.identifier.e-issn | 2045-2322 | es_ES |
dc.relation.publisherversion | https://doi.org/10.1038/srep24439. | es_ES |
dc.identifier.journal | Scientific reports | es_ES |
dc.repisalud.institucion | CNIO | es_ES |
dc.repisalud.orgCNIO | CNIO::Unidades técnicas::Unidad de Espectroscopía y RMN | es_ES |
dc.relation.projectID | info:eu_repo/grantAgreement/ES/S2010-BMD-2457 | es_ES |
dc.relation.projectID | info:eu_repo/grantAgreement/EC/FP7/261863 | es_ES |
dc.rights.accessRights | open access | es_ES |