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dc.contributor.authorPucheta-Martínez, Encarna
dc.contributor.authorSaladino, Giorgio
dc.contributor.authorMorando, Maria Agnese
dc.contributor.authorMartinez Torrecuadrada, Jorge Luis 
dc.contributor.authorLelli, Moreno
dc.contributor.authorSutto, Ludovico
dc.contributor.authorD'Amelio, Nicola
dc.contributor.authorGervasio, Francesco Luigi
dc.date.accessioned2019-11-04T11:26:39Z
dc.date.available2019-11-04T11:26:39Z
dc.date.issued2016-04-11
dc.identifier.citationSci Rep. 2016;6:24235es_ES
dc.identifier.issn2045-2322es_ES
dc.identifier.urihttp://hdl.handle.net/20.500.12105/8555
dc.description.abstractPhosphorylation of the activation loop is a fundamental step in the activation of most protein kinases. In the case of the Src tyrosine kinase, a prototypical kinase due to its role in cancer and its historic importance, phosphorylation of tyrosine 416 in the activation loop is known to rigidify the structure and contribute to the switch from the inactive to a fully active form. However, whether or not phosphorylation is able per-se to induce a fully active conformation, that efficiently binds ATP and phosphorylates the substrate, is less clear. Here we employ a combination of solution NMR and enhanced-sampling molecular dynamics simulations to fully map the effects of phosphorylation and ATP/ADP cofactor loading on the conformational landscape of Src tyrosine kinase. We find that both phosphorylation and cofactor binding are needed to induce a fully active conformation. What is more, we find a complex interplay between the A-loop and the hinge motion where the phosphorylation of the activation-loop has a significant allosteric effect on the dynamics of the C-lobe.es_ES
dc.description.sponsorshipFinancial support by the Access to Research Infrastructures activity in the 7th Framework Programme of the EC (Project number: 261863, Bio-NMR) for conducting the NMR experiments is gratefully acknowledged. We also acknowledge EPSRC, grant [EP/M013898/1], the MRC Biomedical NMR Center of London for generous NMR time allocation, the PRACE Research Infrastructure (Hornet, Curie & MareNostrum), the e-Infrastructure South (Emerald) and the HECBioSim (EPSRC grant EP/L000253/1) for computational resources.es_ES
dc.language.isoenges_ES
dc.publisherNature Publishing Group es_ES
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/4.0/*
dc.subject.meshAdenosine Triphosphate es_ES
dc.subject.meshAllosteric Regulation es_ES
dc.subject.meshBinding Sites es_ES
dc.subject.meshCatalytic Domain es_ES
dc.subject.meshHumans es_ES
dc.subject.meshMolecular Dynamics Simulation es_ES
dc.subject.meshNuclear Magnetic Resonance, Biomolecular es_ES
dc.subject.meshPhosphorylation es_ES
dc.subject.meshThermodynamics es_ES
dc.subject.meshTyrosine es_ES
dc.subject.meshsrc-Family Kinases es_ES
dc.titleAn Allosteric Cross-Talk Between the Activation Loop and the ATP Binding Site Regulates the Activation of Src Kinasees_ES
dc.typejournal articlees_ES
dc.rights.licenseAtribución-NoComercial-CompartirIgual 4.0 Internacional*
dc.identifier.pubmedID27063862es_ES
dc.format.volume6es_ES
dc.format.number1es_ES
dc.format.page24235es_ES
dc.identifier.doi10.1038/srep24235es_ES
dc.contributor.funderEngineering and Physical Sciences Research Council (Reino Unido) 
dc.contributor.funderUnión Europea. Comisión Europea. European Research Council (ERC) 
dc.contributor.funderEngineering and Physical Sciences Research Council (Reino Unido) 
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://10.1038/srep24235.es_ES
dc.identifier.journalScientific reportses_ES
dc.repisalud.institucionCNIOes_ES
dc.repisalud.orgCNIOCNIO::Unidades técnicas::Antiguas CNIOes_ES
dc.relation.projectIDinfo:eu_repo/grantAgreement/EC/FP7/261863es_ES
dc.rights.accessRightsopen accesses_ES


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Atribución-NoComercial-CompartirIgual 4.0 Internacional
This item is licensed under a: Atribución-NoComercial-CompartirIgual 4.0 Internacional