title: Crystallization and preliminary X-ray analysis of mycophenolic acid-resistant and mycophenolic acid-sensitive forms of IMP dehydrogenase from the human fungal pathogen Cryptococcus.
abstract: Fungal human pathogens such as Cryptococcus neoformans are becoming an increasingly prevalent cause of human morbidity and mortality owing to the increasing numbers of susceptible individuals. The few antimycotics available to combat these pathogens usually target fungal-specific cell-wall or membrane-related components; however, the number of these targets is limited. In the search for new targets and lead compounds, C. neoformans has been found to be susceptible to mycophenolic acid through its target inosine monophosphate dehydrogenase (IMPDH); in contrast, a rare subtype of the related C. gattii is naturally resistant. Here, the expression, purification, crystallization and preliminary crystallographic analysis of IMPDH complexed with IMP and NAD+ is reported for both of these Cryptococcus species. The crystals of IMPDH from both sources had the symmetry of the tetragonal space group I422 and diffracted to a resolution of 2.5 A for C. neoformans and 2.6 A for C. gattii.
authors.affiliation: Centre for Infectious Disease Research, School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD 4072, Australia.
authors.forename: Carl A
authors.initials: CA
authors.lastname: Morrow
authors.forename: Anna
authors.initials: A
authors.lastname: Stamp
authors.forename: Eugene
authors.initials: E
authors.lastname: Valkov
authors.forename: Bostjan
authors.initials: B
authors.lastname: Kobe
authors.forename: James A
authors.initials: JA
authors.lastname: Fraser
mesh_terms: D003455:Cryptococcus neoformans / Q000187:drug effects / Q000201:enzymology*; D003460:Crystallization; D018360:Crystallography, X-Ray; D025141:Drug Resistance, Fungal / Q000187:drug effects; D007168:IMP Dehydrogenase / Q000737:chemistry*; D007291:Inosine Monophosphate / Q000737:chemistry; D009173:Mycophenolic Acid / Q000494:pharmacology*
chemical_list: D007291:Inosine Monophosphate; D007168:IMP Dehydrogenase; D009173:Mycophenolic Acid
references.citation: Biochemistry. 2000 Apr 18;39(15):4533-42
references.pmid: 10758003
references.citation: Cell. 1996 Jun 14;85(6):921-30
references.pmid: 8681386
references.citation: Biochemistry. 2005 Dec 20;44(50):16695-700
references.pmid: 16342959
references.citation: Chem Rev. 2009 Jul;109(7):2903-28
references.pmid: 19480389
references.citation: Curr Opin Drug Discov Devel. 2007 Jul;10(4):403-12
references.pmid: 17659481
references.citation: Biochemistry. 2008 Aug 19;47(33):8689-96
references.pmid: 18642884
references.citation: Immunopharmacology. 2000 May;47(2-3):85-118
references.pmid: 10878285
references.citation: J Biol Chem. 2003 Aug 1;278(31):28470-8
references.pmid: 12746440
references.citation: Curr Med Chem. 1999 Jul;6(7):537-43
references.pmid: 10390599
references.citation: Acta Crystallogr D Biol Crystallogr. 2010 Feb;66(Pt 2):125-32
references.pmid: 20124692
references.citation: Science. 1989 Apr 7;244(4900):41-7
references.pmid: 2649979
references.citation: J Biol Chem. 2005 Mar 25;280(12):11295-302
references.pmid: 15665003
references.citation: J Biol Chem. 2002 Dec 27;277(52):50654-9
references.pmid: 12235158
references.citation: AIDS. 2009 Feb 20;23(4):525-30
references.pmid: 19182676
references.citation: BMC Cell Biol. 2005 May 04;6(1):24
references.pmid: 15869715
references.citation: AIDS Res Hum Retroviruses. 2005 Feb;21(2):116-24
references.pmid: 15725750
references.citation: J Biol Chem. 2001 Aug 31;276(35):32905-16
references.pmid: 11441018
references.citation: J Biol Chem. 2001 Dec 7;276(49):46237-42
references.pmid: 11535588
references.citation: Biochem J. 1977 Jul 15;166(1):1-10
references.pmid: 197916
references.citation: J Biol Chem. 2004 Sep 24;279(39):40320-7
references.pmid: 15269207