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dc.contributor.authorMenegazzi, Marta
dc.contributor.authorMariotto, Sofia
dc.contributor.authorDal Bosco, Martina
dc.contributor.authorDarra, Elena
dc.contributor.authorVaiana, Nadia
dc.contributor.authorShoji, Kazuo
dc.contributor.authorSafwat, Abdel Azeim
dc.contributor.authorMarechal, Jean Didier
dc.contributor.authorPerahia, David
dc.contributor.authorSuzuki, Hisanori
dc.contributor.authorRomeo, Sergio
dc.date.accessioned2016-01-19T13:23:27Z
dc.date.available2016-01-19T13:23:27Z
dc.date.issued2013-12-10
dc.identifier.citationMenegazzi M, Mariotto S, Dal Bosco M, Darra E, Vaiana N, et al. (2013) Direct interaction of natural and synthetic catechins with signal transducer activator of transcription 1 affects both its phosphorylation and activity. FEBS Journal 281: 724–738. Available: http://dx.doi.org/10.1111/febs.12618.
dc.identifier.issn1742-464X
dc.identifier.pmid24255956
dc.identifier.doi10.1111/febs.12618
dc.identifier.urihttp://hdl.handle.net/10754/594188
dc.description.abstractOur previous studies showed that (-)-epigallocatechin-3-gallate (EGCG) inhibits signal transducer activator of transcription 1 (STAT1) activation. Since EGCG may be a promising lead compound for new anti-STAT1 drug design, 15 synthetic catechins, characterized by the (-)-gallocatechin-3-gallate stereochemistry, were studied in the human mammary MDA-MB-231 cell line to identify the minimal structural features that preserve the anti-STAT1 activity. We demonstrate that the presence of three hydroxyl groups of B ring and one hydroxyl group in D ring is essential to preserve their inhibitory action. Moreover, a possible molecular target of these compounds in the STAT1 pathway was investigated. Our results demonstrate a direct interaction between STAT1 protein and catechins displaying anti-STAT1 activity. In particular, surface plasmon resonance (SPR) analysis and molecular modeling indicate the presence of two putative binding sites (a and b) with different affinity. Based on docking data, site-directed mutagenesis was performed, and interaction of the most active catechins with STAT1 was studied with SPR to test whether Gln518 on site a and His568 on site b could be important for the catechin-STAT1 interaction. Data indicate that site b has higher affinity for catechins than site a as the highest affinity constant disappears in the H568ASTAT1 mutant. Furthermore, Janus kinase 2 (JAK2) kinase assay data suggest that the contemporary presence in vitro of STAT1 and catechins inhibits JAK2-elicited STAT1 phosphorylation. The very tight catechin-STAT1 interaction prevents STAT1 phosphorylation and represents a novel, specific and efficient molecular mechanism for the inhibition of STAT1 activation. © Copyright 2014 Federation of European Biochemical Societies. All rights reserved.
dc.description.sponsorshipThis work was supported by Fondo Unico per la Ricerca (FUR)/Menegazzi, Ministero dell'Istruzione, dell'Universita e della Ricerca (MIUR), Rome, Italy.
dc.publisherWiley
dc.subjectGallocatechin-3-gallate
dc.subjectMolecular docking
dc.subjectSite-directed mutagenesis
dc.subjectSTAT1
dc.subjectSurface plasmon resonance
dc.subjectSynthetic catechins
dc.titleDirect interaction of natural and synthetic catechins with signal transducer activator of transcription 1 affects both its phosphorylation and activity
dc.typeArticle
dc.contributor.departmentKAUST Catalysis Center (KCC)
dc.identifier.journalFEBS Journal
dc.contributor.institutionDepartment of Life and Reproduction Sciences; Biochemistry Section; University of Verona; Italy
dc.contributor.institutionDipartimento di Scienze Farmaceutiche; University of Milano; Italy
dc.contributor.institutionDepartment of Human Arts and Sciences; University of Saitama; Japan
dc.contributor.institutionDepartament de Química; Universitat Autònoma de Barcelona; Bellaterra Spain
dc.contributor.institutionDynamics of Macromolecular Complexes; Laboratoire de Biologie et Pharmacologie Appliquée; Ecole Normale Supérieure de Cachan; France
kaust.personSafwat, Abdel Azeim
dc.date.published-online2013-12-10
dc.date.published-print2014-02


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