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PDBsum entry 1w3o
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Antibiotic resistance
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PDB id
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1w3o
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References listed in PDB file
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Key reference
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Title
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Structural basis of 5-Nitroimidazole antibiotic resistance: the crystal structure of nima from deinococcus radiodurans.
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Authors
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H.K.Leiros,
S.Kozielski-Stuhrmann,
U.Kapp,
L.Terradot,
G.A.Leonard,
S.M.Mcsweeney.
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Ref.
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J Biol Chem, 2004,
279,
55840-55849.
[DOI no: ]
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PubMed id
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Abstract
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5-Nitroimidazole-based antibiotics are compounds extensively used for treating
infections in humans and animals caused by several important pathogens. They are
administered as prodrugs, and their activation depends upon an anaerobic
1-electron reduction of the nitro group by a reduction pathway in the cells.
Bacterial resistance toward these drugs is thought to be caused by decreased
drug uptake and/or an altered reduction efficiency. One class of resistant
strains, identified in Bacteroides, has been shown to carry Nim genes (NimA, -B,
-C, -D, and -E), which encode for reductases that convert the nitro group on the
antibiotic into a non-bactericidal amine. In this paper, we have described the
crystal structure of NimA from Deinococcus radiodurans (drNimA) at 1.6 A
resolution. We have shown that drNimA is a homodimer in which each monomer
adopts a beta-barrel fold. We have identified the catalytically important His-71
along with the cofactor pyruvate and antibiotic binding sites, all of which are
found at the monomer-monomer interface. We have reported three additional
crystal structures of drNimA, one in which the antibiotic metronidazole is bound
to the protein, one with pyruvate covalently bound to His-71, and one with
lactate covalently bound to His-71. Based on these structures, a reaction
mechanism has been proposed in which the 2-electron reduction of the antibiotic
prevents accumulation of the toxic nitro radical. This mechanism suggests that
Nim proteins form a new class of reductases, conferring resistance against
5-nitroimidazole-based antibiotics.
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Figure 5.
FIG. 5. a, Fourier difference map (F[o] - F[c]) at 3  with the
pyruvate residue omitted from the refinement of the native
drNimA structure. The finally refined pyruvate is given along
with some surrounding residues. b, a LIGPLOT (41) presentation
of the chemical environments of the pyruvate in the final drNimA
structure, with inter-atomic distances for polar interactions.
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Figure 7.
FIG. 7. Proposed antibiotic resistance mechanism. Step  ,
this is from the native drNimA structure to the covalently bound
pyruvate structure (drNimA-Pyr), an oxidation of His-71 and
pyruvate into a His-71-Pyr residue, a reaction that releases
2e^- and H+. Step  ,
the released electrons can further be used to reduce the
antibiotic. Because the antibiotic gets 2e^-, it prevents
formation of the toxic bactericidal radical  as
given in Fig. 1. Our drNimA-MTR structure seems to be an
intermediate, which is located somewhere along Step in
between the native drNimA and the drNimA-Pyr complex.
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The above figures are
reprinted
by permission from the ASBMB:
J Biol Chem
(2004,
279,
55840-55849)
copyright 2004.
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