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dc.contributor.authorChristopeit, Tony
dc.contributor.authorYang, Ke-Wu
dc.contributor.authorYang, Shao-Kang
dc.contributor.authorLeiros, Hanna-Kirsti S.
dc.date.accessioned2017-03-21T10:55:55Z
dc.date.available2017-03-21T10:55:55Z
dc.date.issued2016-11
dc.description.abstractThe increasing number of pathogens expressing metallo-β-lactamases (MBLs), and in this way achieving resistance to β-lactam antibiotics, is a significant threat to global public health. A promising strategy to treat such resistant pathogens is the co-administration of MBL inhibitors together with β-lactam antibiotics. However, an MBL inhibitor suitable for clinical use has not yet been identified. Verona integron-encoded metallo-β-lactamase 2 (VIM-2) is a widespread MBL with a broad substrate spectrum and hence is an interesting drug target for the treatment of β-lactam-resistant infections. In this study, three triazolylthio­acetamides were tested as inhibitors of VIM-2. One of the tested compounds showed clear inhibition of VIM-2, with an IC50 of 20 µM. The crystal structure of the inhibitor in complex with VIM-2 was obtained by DMSO-free co-crystallization and was solved at a resolution of 1.50 Å. To our knowledge, this is the first structure of a triazolylthioacetamide inhibitor in complex with an MBL. Analysis of the structure shows that the inhibitor binds to the two zinc ions in the active site of VIM-2 and revealed detailed information on the interactions involved. Furthermore, the crystal structure showed that binding of the inhibitor induced a conformational change of the conserved residue Trp87.en_US
dc.description.sponsorshipThis work was supported by the Tromsø Research Foundation and the Research Council of Norway (project Nos. 218539, SYNKNOYT 2011, and 213808, FRIMEDBIO 2011) and by grants 21272186, 21572179 and 81361138018 (to K-WY) from the National Natural Science Foundation of China.en_US
dc.descriptionSource: <a href=http://dx.doi.org/10.1107/S2053230X16016113>doi: 10.1107/S2053230X16016113</a>en_US
dc.identifier.citationChristopeit T, Yang, Yang, Leiros H. The structure of the metallo-β-lactamase VIM-2 in complex with a triazolylthioacetamide inhibitor. Acta Crystallographica. Section F : Structural Biology and Crystallization Communications. 2016;72(11):813-819en_US
dc.identifier.cristinIDFRIDAID 1421444
dc.identifier.doi10.1107/S2053230X16016113
dc.identifier.issn1744-3091
dc.identifier.urihttps://hdl.handle.net/10037/10793
dc.language.isoengen_US
dc.publisherInternational Union of Crystallographyen_US
dc.relation.journalActa Crystallographica. Section F : Structural Biology and Crystallization Communications
dc.relation.projectIDinfo:eu-repo/grantAgreement/RCN/SYNKNØYT/218539/Norway/High Throughput Pipeline for Structure Based Drug Design, and Antibiotic Resistance Enzymes in particularen_US
dc.relation.projectIDinfo:eu-repo/grantAgreement/RCN/FRIMEDBIO/213808/Norway/Combating Antibiotic Resistance - Development of Inhibitors against Antibiotic Resistance Enzymesen_US
dc.rights.accessRightsopenAccessen_US
dc.subjectVDP::Matematikk og Naturvitenskap: 400::Kjemi: 440en_US
dc.subjectVDP::Mathematics and natural science: 400::Chemistry: 440en_US
dc.titleThe structure of the metallo-β-lactamase VIM-2 in complex with a triazolylthioacetamide inhibitoren_US
dc.typeJournal articleen_US
dc.typeTidsskriftartikkelen_US
dc.typePeer revieweden_US


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