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dc.contributor.authorIglesias Bexiga, Manuel
dc.contributor.authorPalencia, Andrés
dc.contributor.authorCorbi Verge, Carles
dc.contributor.authorMartín-Malpartida, Pau
dc.contributor.authorBlanco, Francisco J.
dc.contributor.authorMacías, María J.
dc.contributor.authorSánchez Cobos, Eva María 
dc.contributor.authorLuque Fernández, Irene 
dc.date.accessioned2025-01-22T10:21:10Z
dc.date.available2025-01-22T10:21:10Z
dc.date.issued2019-10-21
dc.identifier.citationIglesias-Bexiga M, Palencia A, Corbi-Verge C, Martin-Malpartida P, Blanco FJ, Macias MJ, Cobos ES, Luque I. Binding site plasticity in viral PPxY Late domain recognition by the third WW domain of human NEDD4. Sci Rep. 2019 Oct 21;9(1):15076. doi: 10.1038/s41598-019-50701-3. PMID: 31636332; PMCID: PMC6803667.es_ES
dc.identifier.urihttps://hdl.handle.net/10481/99958
dc.description.abstractThe recognition of PPxY viral Late domains by the third WW domain of the HECT-E3 ubiquitin ligase NEDD4 (hNEDD4-WW3) is essential for the completion of the budding process of numerous enveloped viruses, including Ebola, Marburg, HTLV1 or Rabies. hNEDD4-WW3 has been validated as a promising target for the development of novel host-oriented broad spectrum antivirals. Nonetheless, finding inhibitors with good properties as therapeutic agents remains a challenge since the key determinants of binding affinity and specificity are still poorly understood. We present here a detailed structural and thermodynamic study of the interactions of hNEDD4-WW3 with viral Late domains combining isothermal titration calorimetry, NMR structural determination and molecular dynamics simulations. Structural and energetic differences in Late domain recognition reveal a highly plastic hNEDD4-WW3 binding site that can accommodate PPxY-containing ligands with varying orientations. These orientations are mostly determined by specific conformations adopted by residues I859 and T866. Our results suggest a conformational selection mechanism, extensive to other WW domains, and highlight the functional relevance of hNEDD4-WW3 domain conformational flexibility at the binding interface, which emerges as a key element to consider in the search for potent and selective inhibitors of therapeutic interest.es_ES
dc.description.sponsorshipThis research has been financed by grants BIO2009-13261-C02, BIO2012-39922-CO2 and BIO2016-78746-C2-1-R from the Spanish Ministry of Education and Science (I.L.) including AEI/FEDER EU funds, by CTQ2017-83810-R grant (F.J.B) and by BFU2014-53787-P, the IRB Barcelona and the BBVA Foundation (M.J.M). M.I.B. was a recipient of a research contract from the Spanish Ministry of Education and Science. M.J.M is an ICREA Programme Investigator.es_ES
dc.language.isoenges_ES
dc.publisherEditor Nature Publishing Group UKes_ES
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 Internacional*
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/*
dc.subjectViral Late domainses_ES
dc.subjectHuman NEDD4-WW3 domaines_ES
dc.subjectBinding interfacees_ES
dc.subjectConformational flexibilityes_ES
dc.titleBinding site plasticity in viral PPxY Late domain recognition by the third WW domain of human NEDD4es_ES
dc.typejournal articlees_ES
dc.rights.accessRightsopen accesses_ES
dc.identifier.doihttps://doi.org/10.1038/s41598-019-50701-3
dc.type.hasVersionAOes_ES


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