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PDBsum entry 2fhs
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Oxidoreductase/biosynthetic protein
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PDB id
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2fhs
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References listed in PDB file
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Key reference
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Title
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Structure of acyl carrier protein bound to fabi, The fasii enoyl reductase from escherichia coli.
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Authors
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S.Rafi,
P.Novichenok,
S.Kolappan,
X.Zhang,
C.F.Stratton,
R.Rawat,
C.Kisker,
C.Simmerling,
P.J.Tonge.
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Ref.
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J Biol Chem, 2006,
281,
39285-39293.
[DOI no: ]
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PubMed id
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Abstract
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Acyl carrier proteins play a central role in metabolism by transporting
substrates in a wide variety of pathways including the biosynthesis of fatty
acids and polyketides. However, despite their importance, there is a paucity of
direct structural information concerning the interaction of ACPs with enzymes in
these pathways. Here we report the structure of an acyl-ACP substrate bound to
the Escherichia coli fatty acid biosynthesis enoyl reductase enzyme (FabI),
based on a combination of x-ray crystallography and molecular dynamics
simulation. The structural data are in agreement with kinetic studies on
wild-type and mutant FabIs, and reveal that the complex is primarily stabilized
by interactions between acidic residues in the ACP helix alpha2 and a patch of
basic residues adjacent to the FabI substrate-binding loop. Unexpectedly, the
acyl-pantetheine thioester carbonyl is not hydrogen-bonded to Tyr(156), a
conserved component of the short chain alcohol dehydrogenase/reductase
superfamily active site triad. FabI is a proven target for drug discovery and
the present structure provides insight into the molecular determinants that
regulate the interaction of ACPs with target proteins.
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Figure 4.
FIGURE 4. The structure of ACP bound to FabI following MD
simulations. Final structure of the FabI·ACP complex.
FabI is colored green and ACP is colored cyan. The figure was
made with pymol (64).
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Figure 5.
FIGURE 5. Interactions between FabI and ACP. A,
interactions between ACP (cyan) and FabI (green) at the helix
 2
(ACP)-helix 8 (FabI) interface. B,
interactions between crotonyl-pantetheine and FabI. The
pantetheine (cyan) is hydrogen bonded to residues in FabI helix
8
(green). FabI residues in the conserved active site triad
(Tyr^146, Tyr^156, and Lys^163) are colored yellow. The crotonyl
group of the substrate (cyan) is bound in the s-trans
conformation and the crotonyl carbonyl group is oriented toward
Tyr^146 (yellow). The C-3 carbon of the crotonyl group is 3
Å from the NADH pro4(S) proton (white). In addition, the
NADH ribose (cyan) is hydrogen bonded to Tyr^156 and Lys^163.
The figure was made with pymol (64).
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The above figures are
reprinted
by permission from the ASBMB:
J Biol Chem
(2006,
281,
39285-39293)
copyright 2006.
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