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PDBsum entry 2bv6
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Transcriptional regulator
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PDB id
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2bv6
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References listed in PDB file
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Key reference
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Title
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An oxidation-Sensing mechanism is used by the global regulator mgra in staphylococcus aureus.
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Authors
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P.R.Chen,
T.Bae,
W.A.Williams,
E.M.Duguid,
P.A.Rice,
O.Schneewind,
C.He.
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Ref.
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Nat Chem Biol, 2006,
2,
591-595.
[DOI no: ]
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PubMed id
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Abstract
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Staphylococcus aureus is a human pathogen responsible for most wound and
hospital-acquired infections. The protein MgrA is both an important virulence
determinant during infection and a regulator of antibiotic resistance in S.
aureus. The crystal structure of the MgrA homodimer, solved at 2.86 A, indicates
the presence of a unique cysteine residue located at the interface of the
protein dimer. We discovered that this cysteine residue can be oxidized by
various reactive oxygen species, such as hydrogen peroxide and organic
hydroperoxide. Cysteine oxidation leads to dissociation of MgrA from DNA and
initiation of signaling pathways that turn on antibiotic resistance in S.
aureus. The oxidation-sensing mechanism is typically used by bacteria to counter
challenges of reactive oxygen and nitrogen species. Our study reveals that in S.
aureus, MgrA adopts a similar mechanism but uses it to globally regulate
different defensive pathways.
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Figure 2.
(a) Ribbon representation of the MgrA dimer with one subunit
colored blue and the dyadic mate colored green. The N and C
termini and secondary structural elements of one monomer are
labeled (  ,
-helices;
 ,
-sheets;
W1, the wing region). Numbering is according to MgrA primary
sequence (Supplementary Fig. 4). Potential DNA-interacting basic
residues on the DNA binding domain are shown together with one
ordered sulfate anion per monomer.
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Figure 4.
(a,b) The change in susceptibility of S. aureus strains to
ciprofloxacin (CIP) and vancomycin (VCM) under oxidative stress.
The antibiotic resistance levels were tested in the absence
(-H[2]O[2]) or presence (+H[2]O[2]) of 100  M
H[2]O[2] by a plate sensitivity assay (a) and were also
determined in the absence (-PQ) or presence (+PQ) of 25 M
paraquat by a 96-well plate sensitivity assay (b). Under normal
growth conditions (control) the five strains did not show
noticeable differences. The wild-type strain and the mgrA mutant
strain complemented with pYJ335-His-mgrA showed higher
susceptibility toward CIP and VCM. Under oxidation conditions
both strains showed increased resistance, comparable to that of
the mgrA mutant strain, toward these antibiotics. In control
experiments, the pYJ335-His-mgrAC12S–containing mutant strain
did not change its susceptibility toward CIP and VCM under
normal versus oxidative conditions. (c) Induction of norA, a
gene regulated by mgrA, by oxidative stress. -Galactosidase
activity of strains containing the norA-lacZ reporter fusion was
determined in the wild-type (Newman) and mgrA mutant (  N
 3040)
strains and expressed in MUG units (MUG, 4-methylumbelliferyl-
-D-galactopyranoside;
1 MUG unit = 1 pmol of MUG cleaved by -galactosidase
per min per OD[600]). Empty bars are untreated cultures. Results
are mean  s.d.
from three independent experiments performed in duplicate.
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The above figures are
reprinted
by permission from Macmillan Publishers Ltd:
Nat Chem Biol
(2006,
2,
591-595)
copyright 2006.
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