Mostrar el registro sencillo del ítem

dc.contributor.authorMorando, Maria Agnese
dc.contributor.authorSaladino, Giorgio
dc.contributor.authorD'Amelio, Nicola
dc.contributor.authorPucheta-Martinez, Encarna
dc.contributor.authorLovera, Silvia
dc.contributor.authorLelli, Moreno
dc.contributor.authorLópez-Méndez, Blanca
dc.contributor.authorMarenchino, Marco
dc.contributor.authorCampos Olivas, Ramon 
dc.contributor.authorGervasio, Francesco Luigi
dc.date.accessioned2019-11-11T11:14:51Z
dc.date.available2019-11-11T11:14:51Z
dc.date.issued2016-04-18
dc.identifier.citationSci Rep. 2016;6:24439.es_ES
dc.identifier.issn2045-2322es_ES
dc.identifier.urihttp://hdl.handle.net/20.500.12105/8571
dc.description.abstractUnderstanding 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.sponsorshipWe 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.isoenges_ES
dc.publisherNature Publishing Group es_ES
dc.type.hasVersionVoRes_ES
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/4.0/*
dc.subject.meshAntineoplastic Agents es_ES
dc.subject.meshImatinib Mesylate es_ES
dc.subject.meshLigands es_ES
dc.subject.meshMagnetic Resonance Imaging es_ES
dc.subject.meshMolecular Conformation es_ES
dc.subject.meshMolecular Dynamics Simulation es_ES
dc.subject.meshProtein Binding es_ES
dc.subject.meshSurface Plasmon Resonance es_ES
dc.subject.meshsrc-Family Kinases es_ES
dc.titleConformational Selection and Induced Fit Mechanisms in the Binding of an Anticancer Drug to the c-Src Kinasees_ES
dc.typejournal articlees_ES
dc.rights.licenseAtribución-NoComercial-CompartirIgual 4.0 Internacional*
dc.identifier.pubmedID27087366es_ES
dc.format.volume6es_ES
dc.format.number1es_ES
dc.format.page24439es_ES
dc.identifier.doi10.1038/srep24439es_ES
dc.contributor.funderEngineering and Physical Sciences Research Council (Reino Unido) 
dc.contributor.funderComunidad de Madrid (España) 
dc.contributor.funderEuropean Commission Joint Research Centre European Community (EC)
dc.contributor.funderMedical Research Council (Reino Unido) 
dc.contributor.funderThe Francis Crick Institute 
dc.description.peerreviewedes_ES
dc.identifier.e-issn2045-2322es_ES
dc.relation.publisherversionhttps://doi.org/10.1038/srep24439.es_ES
dc.identifier.journalScientific reportses_ES
dc.repisalud.institucionCNIOes_ES
dc.repisalud.orgCNIOCNIO::Unidades técnicas::Unidad de Espectroscopía y RMNes_ES
dc.relation.projectIDinfo:eu_repo/grantAgreement/ES/S2010-BMD-2457es_ES
dc.relation.projectIDinfo:eu_repo/grantAgreement/EC/FP7/261863es_ES
dc.rights.accessRightsopen accesses_ES


Ficheros en el ítem

Acceso Abierto
Thumbnail
Acceso Abierto
Thumbnail

Este ítem aparece en la(s) siguiente(s) colección(ones)

Mostrar el registro sencillo del ítem

Atribución-NoComercial-CompartirIgual 4.0 Internacional
Este Item está sujeto a una licencia Creative Commons: Atribución-NoComercial-CompartirIgual 4.0 Internacional