Browsing by Author "Modi, Gyan"
Now showing 1 - 1 of 1
- Results Per Page
- Sort Options
Item Mycobacterium tuberculosis IMPDH in Complexes with Substrates, Products and Antitubercular Compounds(PLoS Biology, 2015-10) Grzyska, Magdalena M.; Kim, Youngchang; Gorla, Suresh K.; Wei, Yang; Mandapati, Kavitha; Zhang, Minjia; Maltseva, Natalia; Modi, Gyan; Boshoff, Helena I. M.; Gu, Minyi; Aldrich, Courtney; Cuny, Gregory D.; Hedstrom, Lizbeth; Joachimiak, AndrzejTuberculosis (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.