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PDBsum entry 2glm
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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 for catalytic and inhibitory mechanisms of beta-Hydroxyacyl-Acyl carrier protein dehydratase (fabz).
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Authors
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L.Zhang,
W.Liu,
T.Hu,
L.Du,
C.Luo,
K.Chen,
X.Shen,
H.Jiang.
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Ref.
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J Biol Chem, 2008,
283,
5370-5379.
[DOI no: ]
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PubMed id
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Abstract
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beta-Hydroxyacyl-acyl carrier protein dehydratase (FabZ) is an important enzyme
for the elongation cycles of both saturated and unsaturated fatty acids
biosyntheses in the type II fatty acid biosynthesis system (FAS II) pathway.
FabZ has been an essential target for the discovery of compounds effective
against pathogenic microbes. In this work, to characterize the catalytic and
inhibitory mechanisms of FabZ, the crystal structures of the FabZ of
Helicobacter pylori (HpFabZ) and its complexes with two newly discovered
inhibitors have been solved. Different from the structures of other bacterial
FabZs, HpFabZ contains an extra short two-turn alpha-helix (alpha4) between
alpha3 and beta3, which plays an important role in shaping the substrate-binding
tunnel. Residue Tyr-100 at the entrance of the tunnel adopts either an open or
closed conformation in the crystal structure. The crystal structural
characterization, the binding affinity determination, and the enzymatic activity
assay of the HpFabZ mutant (Y100A) confirm the importance of Tyr-100 in
catalytic activity and substrate binding. Residue Phe-83 at the exit tunnel was
also refined in two alternative conformations, leading the tunnel to form an
L-shape and U-shape. All these data thus contributed much to understanding the
catalytic mechanism of HpFabZ. In addition, the co-crystal structures of HpFabZ
with its inhibitors have suggested that the enzymatic activity of HpFabZ could
be inhibited either by occupying the entrance of the tunnel or plugging the
tunnel to prevent the substrate from accessing the active site. Our study has
provided some insights into the catalytic and inhibitory mechanisms of FabZ,
thus facilitating antibacterial agent development.
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Figure 5.
FIGURE 5. Stereo view of the omit electron density map
contoured at 1.0  around the compounds.
Residues Tyr-100, Pro-112', and inhibitor are shown as sticks.
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Figure 6.
FIGURE 6. Crystal structures of HpFabZ in complex with
compounds 1 and 2. The dimers that bind to the compounds are
represented. The hydrophobic surface of the active tunnel and
the critical residues that interact with the compounds are also
shown.
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The above figures are
reprinted
by permission from the ASBMB:
J Biol Chem
(2008,
283,
5370-5379)
copyright 2008.
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