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dc.contributor.authorGomez-Gutierrez, Patricia
dc.contributor.authorCampos Muelas, Pedro Manuel
dc.contributor.authorVega, Miguel
dc.contributor.authorPérez González, Juan Jesús
dc.contributor.otherUniversitat Politècnica de Catalunya. Departament d'Enginyeria Química
dc.date.accessioned2017-02-01T09:07:28Z
dc.date.available2017-02-01T09:07:28Z
dc.date.issued2016-11-29
dc.identifier.citationGomez-Gutierrez, P., Campos, P. M., Vega, M., Perez, J. Identification of a novel inhibitory allosteric site of MAP kinases. "PLoS one", 29 Novembre 2016, vol. 11, núm. 11, p. 1-16.
dc.identifier.issn1932-6203
dc.identifier.urihttp://hdl.handle.net/2117/100420
dc.description.abstractIn the present study, we report the discovery of a novel allosteric inhibitory site for p38a, a subclass of the mitogen-activated protein kinases (MAPK) family. The putative site was discovered after inspection of the crystallographic structure of the p38a-MK2 complex. MK2 (MAPK-activated protein kinase 2) is an interesting protein playing a dual role as modulator and substrate of p38a. This intriguing behavior is due to the ability of the two proteins to form distinctive heterodimers when p38a is phosphorylated or not. We hypothesized that the regulatory action of MK2 is due to its capability to keep p38a in an inactive conformation and consequently, we investigated the atomic structure of the p38a-MK2 complex to understand such regulatory behavior at the molecular level. After inspection of the complex structure, two peptides designed from the MK2 regulatory loop in contact with p38a with sequences Tyr1-Ser2-Asn3-His4-Gly5-Leu6 (peptide-1) and [Phe0]-peptide-1 (peptide-2) in their zwitterionic form were investigated for their phosphorylation inhibitory capability in vitro. Since both peptides exhibited inhibitory capability of the p38a kinase mediated phosphorylation of MEF2A, in a subsequent step we pursued the discovery of small molecule peptidomimetics. For this purpose we characterized in detail the peptide-p38a interaction using molecular dynamics simulations, leading to the definition of a pharmacophore for the peptide-protein interaction. This hypothesis was used as query for a in silico screening, leading to the discovery of a fused ring compound with micromolar inhibitory activity. Site-directed mutagenesis studies support that the compound binds to the putative novel allosteric site in p38a.
dc.format.extent16 p.
dc.language.isoeng
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/3.0/es/
dc.subjectÀrees temàtiques de la UPC::Enginyeria química
dc.subject.lcshAllosteric proteins
dc.subject.otherInhibidors de quinases
dc.subject.otherbutxaca al.losterica
dc.subject.otherp38 alfa
dc.titleIdentification of a novel inhibitory allosteric site of MAP kinases
dc.typeArticle
dc.subject.lemacProteïnes quinases -- Inhibidors -- Ús terapèutic
dc.subject.lemacMedicaments -- Desenvolupament
dc.contributor.groupUniversitat Politècnica de Catalunya. GBMI - Grup de Biotecnologia Molecular i Industrial
dc.identifier.doi10.1371/journal.pone.0167379
dc.description.peerreviewedPeer Reviewed
dc.relation.publisherversionhttp://journals.plos.org/plosone/article?id=10.1371/journal.pone.0167379
dc.rights.accessOpen Access
local.identifier.drac19330528
dc.description.versionPostprint (published version)
local.citation.authorGomez-Gutierrez, P.; Campos, P. M.; Vega, M.; Perez, J.
local.citation.publicationNamePLoS one
local.citation.volume11
local.citation.number11
local.citation.startingPage1
local.citation.endingPage16
dc.identifier.pmid27898710


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