title: Crystallization and initial crystallographic analysis of covalent DNA-cleavage complexes of Staphyloccocus aureus DNA gyrase with QPT-1, moxifloxacin and etoposide.
abstract: Fluoroquinolone drugs such as moxifloxacin kill bacteria by stabilizing the normally transient double-stranded DNA breaks created by bacterial type IIA topoisomerases. Previous crystal structures of Staphylococcus aureus DNA gyrase with asymmetric DNAs have had static disorder (with the DNA duplex observed in two orientations related by the pseudo-twofold axis of the complex). Here, 20-base-pair DNA homoduplexes were used to obtain crystals of covalent DNA-cleavage complexes of S. aureus DNA gyrase. Crystals with QPT-1, moxifloxacin or etoposide diffracted to between 2.45 and 3.15 Å resolution. A G/T mismatch introduced at the ends of the DNA duplexes facilitated the crystallization of slightly asymmetric complexes of the inherently flexible DNA-cleavage complexes.
authors.affiliation: Platform Technology and Science, GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, England.
authors.forename: Velupillai
authors.initials: V
authors.lastname: Srikannathasan
authors.affiliation: Platform Technology and Science, GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, England.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Wohlkonig
authors.affiliation: Platform Technology and Science, GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, England.
authors.forename: Anthony
authors.initials: A
authors.lastname: Shillings
authors.affiliation: Platform Technology and Science, GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, England.
authors.forename: Onkar
authors.initials: O
authors.lastname: Singh
authors.affiliation: Antibacterial Discovery Performance Unit, Infectious Diseases Medicines Discovery and Development, GlaxoSmithKline, 1250 Collegeville Road, Collegeville, PA 19426, USA.
authors.forename: Pan F
authors.initials: PF
authors.lastname: Chan
authors.affiliation: Antibacterial Discovery Performance Unit, Infectious Diseases Medicines Discovery and Development, GlaxoSmithKline, 1250 Collegeville Road, Collegeville, PA 19426, USA.
authors.forename: Jianzhong
authors.initials: J
authors.lastname: Huang
authors.affiliation: Antibacterial Discovery Performance Unit, Infectious Diseases Medicines Discovery and Development, GlaxoSmithKline, 1250 Collegeville Road, Collegeville, PA 19426, USA.
authors.forename: Michael N
authors.initials: MN
authors.lastname: Gwynn
authors.affiliation: Platform Technology and Science, GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, England.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Fosberry
authors.affiliation: Platform Technology and Science, GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, England.
authors.forename: Paul
authors.initials: P
authors.lastname: Homes
authors.affiliation: Platform Technology and Science, GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, England.
authors.forename: Martin
authors.initials: M
authors.lastname: Hibbs
authors.affiliation: Platform Technology and Science, GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, England.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Theobald
authors.affiliation: Platform Technology and Science, GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, England.
authors.forename: Claus
authors.initials: C
authors.lastname: Spitzfaden
authors.affiliation: Platform Technology and Science, GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, England.
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Bax
mesh_terms: D001483:Base Sequence; D003460:Crystallization; D018360:Crystallography, X-Ray; D053837:DNA Cleavage; D027081:DNA Gyrase / Q000737:chemistry*; D005047:Etoposide / Q000737:chemistry*; D024841:Fluoroquinolones / Q000737:chemistry*; D006576:Heterocyclic Compounds, 4 or More Rings / Q000737:chemistry*; D008969:Molecular Sequence Data; D000077266:Moxifloxacin; D013141:Spiro Compounds / Q000737:chemistry*; D013211:Staphylococcus aureus / Q000201:enzymology*
chemical_list: D024841:Fluoroquinolones; D006576:Heterocyclic Compounds, 4 or More Rings; C541225:PNU-286607; D013141:Spiro Compounds; D005047:Etoposide; D027081:DNA Gyrase; D000077266:Moxifloxacin
keywords: DNA complex; DNA gyrase; etoposide; fluoroquinolone; topoisomerase