Mycobacterium tuberculosis IMPDH in Complexes with Substrates, Products and Antitubercular Compounds

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dc.contributor.authorGrzyska, Magdalena M.
dc.contributor.authorKim, Youngchang
dc.contributor.authorGorla, Suresh K.
dc.contributor.authorWei, Yang
dc.contributor.authorMandapati, Kavitha
dc.contributor.authorZhang, Minjia
dc.contributor.authorMaltseva, Natalia
dc.contributor.authorModi, Gyan
dc.contributor.authorBoshoff, Helena I. M.
dc.contributor.authorGu, Minyi
dc.contributor.authorAldrich, Courtney
dc.contributor.authorCuny, Gregory D.
dc.contributor.authorHedstrom, Lizbeth
dc.contributor.authorJoachimiak, Andrzej
dc.date.accessioned2020-03-10T17:31:47Z
dc.date.available2020-03-10T17:31:47Z
dc.date.issued2015-10
dc.description.abstractTuberculosis (TB) remains a worldwide problem and the need for new drugs is increasingly more urgent with the emergence of multidrug- and extensively-drug resistant TB. Inosine 5’-monophosphate dehydrogenase 2 (IMPDH2) from Mycobacterium tuberculosis (Mtb) is an attractive drug target. The enzyme catalyzes the conversion of inosine 5’-monophosphate into xanthosine 5’-monophosphate with the concomitant reduction of NAD+ to NADH. This reaction controls flux into the guanine nucleotide pool. We report seventeen selective IMPDH inhibitors with antitubercular activity. The crystal structures of a deletion mutant of MtbIMPDH2 in the apo form and in complex with the product XMP and substrate NAD+ are determined. We also report the structures of complexes with IMP and three structurally distinct inhibitors, including two with antitubercular activity. These structures will greatly facilitate the development of MtbIMPDH2-targeted antibiotics.
dc.identifier.citationCopyright 2015 PLoS Biology. Recommended citation: Makowska-Grzyska, Magdalena, Youngchang Kim, Suresh Kumar Gorla, Yang Wei, Kavitha Mandapati, Minjia Zhang, Natalia Maltseva et al. "Mycobacterium tuberculosis IMPDH in complexes with substrates, products and antitubercular compounds." PLoS One 10, no. 10 (2015): e0138976. doi:10.1371/journal.pone.0138976. URL: https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0138976. Reproduced in accordance with the original publisher's licensing terms and with permission from the authors.
dc.identifier.urihttps://hdl.handle.net/10657/5964
dc.language.isoen_US
dc.publisherPLoS Biology
dc.titleMycobacterium tuberculosis IMPDH in Complexes with Substrates, Products and Antitubercular Compounds
dc.typeArticle

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