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A new crystal structure of the bifunctional antibiotic simocyclinone D8 bound to DNA gyrase gives fresh insight into the mechanism of inhibition
DOI:
10.1016/j.jmb.2014.02.017
PMID:
24594357
Authors:
Stephen
Hearnshaw
(John Innes Centre)
,
Marcus
Edwards
(University of East Anglia)
,
Clare
Stevenson
(John Innes Centre)
,
David
Lawson
(John Innes Centre)
,
Anthony
Maxwell
(John Innes Centre)
Co-authored by industrial partner:
No
Type:
Journal Paper
Journal:
Journal Of Molecular Biology
State:
Published (Approved)
Published:
March 2014
Diamond Proposal Number(s):
1219
,
7641

Abstract: Simocyclinone D8 (SD8) is an antibiotic produced by Streptomyces antibioticus that targets DNA gyrase. A previous structure of SD8 complexed with the N-terminal domain of the DNA gyrase A protein (GyrA) suggested that four SD8 molecules stabilized a tetramer of the protein; subsequent mass spectrometry experiments suggested that a protein dimer with two symmetry-related SD8s was more likely. This work describes the structures of a further truncated form of the GyrA N-terminal domain fragment with and without SD8 bound. The structure with SD8 has the two SD8 molecules bound within the same GyrA dimer. This new structure is entirely consistent with the mutations in GyrA that confer SD8 resistance and, by comparison with a new apo structure of the GyrA N-terminal domain, reveals the likely conformation changes that occur upon SD8 binding and the detailed mechanism of SD8 inhibition of gyrase. Isothermal titration calorimetry experiments are consistent with the crystallography results and further suggest that a previously observed complex between SD8 and GyrB is ~ 1000-fold weaker than the interaction with GyrA.
Journal Keywords: Anti-Bacterial; Coumarins; Crystallography; X-Ray; DNA; Drug; Bacterial; Escherichia; Glycosides; Models; Molecular; Protein; Quaternary; Protein; Secondary; Protein; Tertiary; Topoisomerase II Inhibitors
Diamond Keywords: Bacteria; Enzymes
Subject Areas:
Biology and Bio-materials,
Chemistry,
Medicine
Instruments:
I04-1-Macromolecular Crystallography (fixed wavelength)
,
I24-Microfocus Macromolecular Crystallography
Added On:
19/03/2014 12:22
Documents:
1-s2.0-S0022283614000990-main.pdf
Discipline Tags:
Pathogens
Infectious Diseases
Health & Wellbeing
Biochemistry
Chemistry
Structural biology
Drug Discovery
Life Sciences & Biotech
Technical Tags:
Diffraction
Macromolecular Crystallography (MX)