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PDBsum entry 2fu9
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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 insights into the design of inhibitors for the l1 metallo-Beta-Lactamase from stenotrophomonas maltophilia.
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Authors
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L.Nauton,
R.Kahn,
G.Garau,
J.F.Hernandez,
O.Dideberg.
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Ref.
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J Mol Biol, 2008,
375,
257-269.
[DOI no: ]
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PubMed id
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Abstract
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One mechanism by which bacteria can escape the action of beta-lactam antibiotics
is the production of metallo-beta-lactamases. Inhibition of these enzymes should
restore the action of these widely used antibiotics. The tetrameric enzyme L1
from Stenotrophomonas maltophilia was used as a model system to determine a
series of high-resolution crystal structures of apo, mono and bi-metal
substituted proteins as well as protein-inhibitor complexes. Unexpectedly,
although the apo structure revealed only few significant structural differences
from the holo structure, some inhibitors were shown to induce amino acid
side-chain rotations in the tightly packed active site. Moreover, one inhibitor
employs a new binding mode in order to interact with the di-zinc center. This
structural information could prove essential in the process of elucidation of
the mode of interaction between a putative lead compound and
metallo-beta-lactamases, one of the main steps in structure-based drug design.
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Figure 1.
Figure 1. Chemical formulae of the substrate (Nitrocefin) and
inhibitors used in this work. Major components of MBL inhibitors
are colored: the zinc binding group (ZN-B), the hydrophobic
extension (A–E) and the hydrophilic extension (B–E) in
yellow, pink and green, respectively.
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Figure 3.
Figure 3. Stereo views showing the active site of L1 in the
group I structures. Additional water molecules or sulfate ions
are shown compared to Figure 2 when they are in the second shell
of Zn coordination. Zn ligands and amino acid site-chains
forming the active side are displayed. Metal and hydrogen bonds
are in full and broken red lines, respectively. For clarity,
zinc ligands and water molecule labels, and hydrogen bonds
displayed in Figure 2 are not shown.
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The above figures are
reprinted
by permission from Elsevier:
J Mol Biol
(2008,
375,
257-269)
copyright 2008.
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Secondary reference #1
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Title
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The 3-D structure of a zinc metallo-Beta-Lactamase from bacillus cereus reveals a new type of protein fold.
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Authors
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A.Carfi,
S.Pares,
E.Duée,
M.Galleni,
C.Duez,
J.M.Frère,
O.Dideberg.
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Ref.
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Embo J, 1995,
14,
4914-4921.
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PubMed id
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Secondary reference #2
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Title
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A metallo-Beta-Lactamase enzyme in action: crystal structures of the monozinc carbapenemase cpha and its complex with biapenem.
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Authors
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G.Garau,
C.Bebrone,
C.Anne,
M.Galleni,
J.M.Frère,
O.Dideberg.
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Ref.
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J Mol Biol, 2005,
345,
785-795.
[DOI no: ]
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PubMed id
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Figure 2.
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Figure 7.
Figure 7. Scheme of the proposed mechanism of β-lactam
hydrolysis by CphA, as deduced from the structures described
here.
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The above figures are
reproduced from the cited reference
with permission from Elsevier
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