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dc.contributor.authorDias, Marcio Vinicius Bertacine
dc.contributor.authorVasconcelos, Igor Bordin
dc.contributor.authorPrado, Adriane Michele Xavier
dc.contributor.authorFadel, Valmir
dc.contributor.authorBasso, Luiz Augusto
dc.contributor.authorDe Azevedo, Walter Filgueira
dc.contributor.authorSantos, Diogenes Santiago
dc.date.accessioned2014-05-20T15:22:57Z
dc.date.available2014-05-20T15:22:57Z
dc.date.issued2007-09-01
dc.identifierhttp://dx.doi.org/10.1016/j.jsb.2007.04.009
dc.identifier.citationJournal of Structural Biology. San Diego: Academic Press Inc. Elsevier B.V., v. 159, n. 3, p. 369-380, 2007.
dc.identifier.issn1047-8477
dc.identifier.urihttp://hdl.handle.net/11449/33834
dc.description.abstractThe resumption of tuberculosis led to an increased need to understand the molecular mechanisms of drug action and drug resistance, which should provide significant insight into the development of newer compounds. Isoniazid (INH), the most prescribed drug to treat TB, inhibits an NADH-dependent enoyl-acyl carrier protein reductase (InhA) that provides precursors of mycolic acids, which are components of the mycobacterial cell wall. InhA is the major target of the mode of action of isoniazid. INH is a pro-drug that needs activation to form the inhibitory INH-NAD adduct. Missense mutations in the inhA structural gene have been identified in clinical isolates of Mycobacterium tuberculosis resistant to INH. To understand the mechanism of resistance to INH, we have solved the structure of two InhA mutants (121V and S94A), identified in INH-resistant clinical isolates, and compare them to INH-sensitive WT InhA structure in complex with the INH-NAD adduct. We also solved the structure of unliganded INH-resistant S94A protein, which is the first report on apo form of InhA. The salient features of these structures are discussed and should provide structural information to improve our understanding of the mechanism of action of, and resistance to, INH in M. tuberculosis. The unliganded structure of InhA allows identification of conformational changes upon ligand binding and should help structure-based drug design of more potent antimycobacterial agents. (c) 2007 Elsevier B.V. All rights reserved.en
dc.format.extent369-380
dc.language.isoeng
dc.publisherElsevier B.V.
dc.relation.ispartofJournal of Structural Biology
dc.sourceWeb of Science
dc.subjectMycobacterium tuberculosispt
dc.subjectInhApt
dc.subjectCrystal structurept
dc.subjectisoniazidpt
dc.subjectdrug resistancept
dc.subjectEnoyl-ACP reductasept
dc.titleCrystallographic studies on the binding of isonicotinyl-NAD adduct to wild-type and isoniazid resistant 2-trans-enoyl-ACP (CoA) reductase from Mycobacterium tuberculosisen
dc.typeArtigo
dcterms.licensehttp://www.elsevier.com/about/open-access/open-access-policies/article-posting-policy
dcterms.rightsHolderElsevier B.V.
dc.contributor.institutionPontifícia Universidade Católica do Rio de Janeiro (PUC-Rio)
dc.contributor.institutionUniversidade Estadual Paulista (UNESP)
dc.contributor.institutionPontificia Univ Catolica Rio Grande do Sul
dc.description.affiliationPontificia Univ Catolica Rio de Janeiro, Fac Biociencias, BR-90619900 Porto Alegre, RS, Brazil
dc.description.affiliationUNESP, Dept Fis, Programa Posgrad Biofis Mol, BR-15054000 Sao Jose do Rio Preto, SP, Brazil
dc.description.affiliationPontificia Univ Catolica Rio Grande do Sul, Inst Pesquisas Biomed, Ctr Pesquisa Biol Mol & Func, Porto Alegre, RS, Brazil
dc.description.affiliationUnespUNESP, Dept Fis, Programa Posgrad Biofis Mol, BR-15054000 Sao Jose do Rio Preto, SP, Brazil
dc.identifier.doi10.1016/j.jsb.2007.04.009
dc.identifier.wosWOS:000249472500005
dc.rights.accessRightsAcesso restrito
unesp.campusUniversidade Estadual Paulista (UNESP), Instituto de Biociências Letras e Ciências Exatas, São José do Rio Pretopt
dc.identifier.lattes2835029061696580
unesp.author.lattes2835029061696580
dc.relation.ispartofjcr3.433
dc.relation.ispartofsjr3,948
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