title: Mycobacterium tuberculosis IMPDH in Complexes with Substrates, Products and Antitubercular Compounds.
abstract: Tuberculosis (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.
authors.affiliation: Center for Structural Genomics of Infectious Diseases, University of Chicago, Chicago, IL, United States of America.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Makowska-Grzyska
authors.affiliation: Center for Structural Genomics of Infectious Diseases, University of Chicago, Chicago, IL, United States of America; Structural Biology Center, Biosciences, Argonne National Laboratory, 9700 S Cass Ave. Argonne, IL, United States of America.
authors.forename: Youngchang
authors.initials: Y
authors.lastname: Kim
authors.affiliation: Department of Biology, Brandeis University, 415 South St. Waltham, MA, United States of America.
authors.forename: Suresh Kumar
authors.initials: SK
authors.lastname: Gorla
authors.affiliation: Department of Biology, Brandeis University, 415 South St. Waltham, MA, United States of America.
authors.forename: Yang
authors.initials: Y
authors.lastname: Wei
authors.affiliation: Department of Biology, Brandeis University, 415 South St. Waltham, MA, United States of America.
authors.forename: Kavitha
authors.initials: K
authors.lastname: Mandapati
authors.affiliation: Department of Biology, Brandeis University, 415 South St. Waltham, MA, United States of America.
authors.forename: Minjia
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Center for Structural Genomics of Infectious Diseases, University of Chicago, Chicago, IL, United States of America.
authors.forename: Natalia
authors.initials: N
authors.lastname: Maltseva
authors.affiliation: Department of Biology, Brandeis University, 415 South St. Waltham, MA, United States of America.
authors.forename: Gyan
authors.initials: G
authors.lastname: Modi
authors.affiliation: Tuberculosis Research Section, National Institute of Allergy and Infectious Diseases, Bethesda, MD, United States of America.
authors.forename: Helena I
authors.initials: HI
authors.lastname: Boshoff
authors.affiliation: Center for Structural Genomics of Infectious Diseases, University of Chicago, Chicago, IL, United States of America.
authors.forename: Minyi
authors.initials: M
authors.lastname: Gu
authors.affiliation: Center for Drug Design, Academic Health Center, University of Minnesota, 516 Delaware St. SE, Minneapolis, MN, United States of America.
authors.forename: Courtney
authors.initials: C
authors.lastname: Aldrich
authors.affiliation: Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, 549A Science and Research Building 2, Houston, TX, United States of America; Department of Chemistry, Brandeis University, 415 South St. Waltham, MA, United States of America.
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Cuny
authors.affiliation: Department of Biology, Brandeis University, 415 South St. Waltham, MA, United States of America; Department of Chemistry, Brandeis University, 415 South St. Waltham, MA, United States of America.
authors.forename: Lizbeth
authors.initials: L
authors.lastname: Hedstrom
authors.affiliation: Center for Structural Genomics of Infectious Diseases, University of Chicago, Chicago, IL, United States of America; Structural Biology Center, Biosciences, Argonne National Laboratory, 9700 S Cass Ave. Argonne, IL, United States of America.
authors.forename: Andrzej
authors.initials: A
authors.lastname: Joachimiak
mesh_terms: D000995:Antitubercular Agents / Q000378:metabolism / Q000494:pharmacology*; D001665:Binding Sites; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000201:enzymology*; D009243:NAD / Q000378:metabolism; D011485:Protein Binding
chemical_list: D000995:Antitubercular Agents; D004791:Enzyme Inhibitors; D009243:NAD; D007168:IMP Dehydrogenase