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dc.contributor.authorPacheco García, Juan Luis 
dc.contributor.authorPalomino Morales, Rogelio Jesús 
dc.contributor.authorMesa-Torres, Noel
dc.contributor.authorPey Rodríguez, Ángel Luis 
dc.date.accessioned2021-10-29T11:47:25Z
dc.date.available2021-10-29T11:47:25Z
dc.date.issued2021-10
dc.identifier.citationPacheco García, J.L. ..[et al.] Structural basis of the pleiotropic and specific phenotypic consequences of missense mutations in the multifunctional NAD(P)H:quinone oxidoreductase 1 and their pharmacological rescu. Redox Biology 46 (2021) 102112. [https://doi.org/10.1016/j.redox.2021.102112]es_ES
dc.identifier.urihttp://hdl.handle.net/10481/71178
dc.descriptionJLP-G and ALP were supported by the ERDF/Spanish Ministry of Science, Innovation and Universities-State Research Agency (Grant RTI2018-096246-B-I00) and Consejeria de Economia, Conocimiento, Empresas y Universidad, Junta de Andalucia (Grants P11-CTS-7187 and P18-RT-2413) . NM-T was supported by Aula FUNCANIS-UGR. ES was supported by the ERDF/Spanish Ministry of Science, Innovation and Universities-State Research Agency (Grant SAF2015-69796) . Access to an EU_FT-ICR_MS network installation was funded by the EU Horizon 2020 grant 731077. EA-C and MM were supported by the Spanish Ministry of Science and Innovation-State Research Agency (Grant PID2019-103901 GB-I00) and Gobierno de Aragon-FEDER (Grant E35_20R) . Support of the BioCeV center (CZ.1.05/1.1.00/02.0109) and the CMS/CIISB facility (MEYS CZ-LM2018127) is also gratefully acknowledged. ANN was supported by grants BT/PR26099/BID/7/811/2017 from Department of Biotechnology (DBT, India) and MTR/2019/000392 from Science, Engineering and Research Board (SERB, India) .es_ES
dc.description.abstractThe multifunctional nature of human flavoproteins is critically linked to their ability to populate multiple conformational states. Ligand binding, post-translational modifications and disease-associated mutations can reshape this functional landscape, although the structure-function relationships of these effects are not well understood. Herein, we characterized the structural and functional consequences of two mutations (the cancer associated P187S and the phosphomimetic S82D) on different ligation states which are relevant to flavin binding, intracellular stability and catalysis of the disease-associated NQO1 flavoprotein. We found that these mutations affected the stability locally and their effects propagated differently through the protein structure depending both on the nature of the mutation and the ligand bound, showing directional preference from the mutated site and leading to specific phenotypic manifestations in different functional traits (FAD binding, catalysis and inhibition, intracellular stability and pharmacological response to ligands). Our study thus supports that pleitropic effects of disease-causing mutations and phosphorylation events on human flavoproteins may be caused by longrange structural propagation of stability effects to different functional sites that depend on the ligation-state and site-specific perturbations. Our approach can be of general application to investigate these pleiotropic effects at the flavoproteome scale in the absence of high-resolution structural models.es_ES
dc.description.sponsorshipERDF/Spanish Ministry of Science, Innovation and Universities-State Research Agency RTI2018-096246-B-I00- SAF2015-69796es_ES
dc.description.sponsorshipJunta de Andalucia P11-CTS-7187- P18-RT-2413es_ES
dc.description.sponsorshipAula FUNCANIS-UGRes_ES
dc.description.sponsorshipEuropean Commission 731077es_ES
dc.description.sponsorshipSpanish Ministry of Science and Innovation-State Research Agency PID2019-103901 GB-I00es_ES
dc.description.sponsorshipGobierno de Aragon-FEDER E35_20Res_ES
dc.description.sponsorshipBioCeV center CZ.1.05/1.1.00/02.0109es_ES
dc.description.sponsorshipCMS/CIISB facility MEYS CZ-LM2018127es_ES
dc.description.sponsorshipDepartment of Biotechnology (DBT) India BT/PR26099/BID/7/811/2017es_ES
dc.description.sponsorshipScience, Engineering and Research Board (SERB, India) MTR/2019/000392es_ES
dc.language.isoenges_ES
dc.publisherElsevieres_ES
dc.rightsAtribución 3.0 España*
dc.rights.urihttp://creativecommons.org/licenses/by/3.0/es/*
dc.subjectFlavoproteines_ES
dc.subjectMultifunctional proteinses_ES
dc.subjectLigand bindinges_ES
dc.subjectDisease-causing mutationes_ES
dc.subjectPost-translational modificationes_ES
dc.subjectNQO1es_ES
dc.titleStructural basis of the pleiotropic and specific phenotypic consequences of missense mutations in the multifunctional NAD(P)H:quinone oxidoreductase 1 and their pharmacological rescuees_ES
dc.typeinfo:eu-repo/semantics/articlees_ES
dc.rights.accessRightsinfo:eu-repo/semantics/openAccesses_ES
dc.identifier.doi10.1016/j.redox.2021.102112
dc.type.hasVersioninfo:eu-repo/semantics/publishedVersiones_ES


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