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PDBsum entry 2jch
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Drug-binding protein
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PDB id
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2jch
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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 and mechanistic basis of penicillin-Binding protein inhibition by lactivicins.
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Authors
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P.Macheboeuf,
D.S.Fischer,
T.Brown,
A.Zervosen,
A.Luxen,
B.Joris,
A.Dessen,
C.J.Schofield.
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Ref.
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Nat Chem Biol, 2007,
3,
565-569.
[DOI no: ]
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PubMed id
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Abstract
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Beta-lactam antibiotics, including penicillins and cephalosporins, inhibit
penicillin-binding proteins (PBPs), which are essential for bacterial cell wall
biogenesis. Pathogenic bacteria have evolved efficient antibiotic resistance
mechanisms that, in Gram-positive bacteria, include mutations to PBPs that
enable them to avoid beta-lactam inhibition. Lactivicin (LTV; 1) contains
separate cycloserine and gamma-lactone rings and is the only known natural PBP
inhibitor that does not contain a beta-lactam. Here we show that LTV and a more
potent analog, phenoxyacetyl-LTV (PLTV; 2), are active against clinically
isolated, penicillin-resistant Streptococcus pneumoniae strains.
Crystallographic analyses of S. pneumoniae PBP1b reveal that LTV and PLTV
inhibition involves opening of both monocyclic cycloserine and gamma-lactone
rings. In PBP1b complexes, the ring-derived atoms from LTV and PLTV show a
notable structural convergence with those derived from a complexed cephalosporin
(cefotaxime; 3). The structures imply that derivatives of LTV will be useful in
the search for new antibiotics with activity against beta-lactam-resistant
bacteria.
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Figure 1.
(a) Structures of  -lactam
antibiotics. The conserved -lactam
ring is highlighted in green. (b) Structures of epimeric LTV and
PLTV. (c) Outline mechanism for -lactams
showing formation of the hydrolytically stable acyl-enzyme
complex (for cefotaxime: R, aminothiazolemethoxyoxime; X,
OCOCH[3]). (d) Proposed mechanism of PBP acylation by LTV and
PLTV, involving formation of a stable acyl-enzyme complex whose
structure is closely analogous to that formed by cephalosporins.
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Figure 3.
(a) F[o] – F[c] map (green) contoured at 2.4  ,
generated before inclusion of LTV in the model. (b) F[o] –
F[c] map (green), contoured at 2.4 ,
for the PLTV molecule. Selected active site residues are shown
as sticks; LTV and PLTV backbones are shown in blue. Notably,
ester link is present between the Ser460 side chain and the
carbonyl of the LTV/PLTV cycloserine ring, and both cycloserine
and lactone rings of the inhibitors are open. Figure was
prepared using PyMOL (http://pymol.sourceforge.net/).
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The above figures are
reprinted
by permission from Macmillan Publishers Ltd:
Nat Chem Biol
(2007,
3,
565-569)
copyright 2007.
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