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PDBsum entry 1ndf
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Contents |
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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Crystal structure of carnitine acetyltransferase and implications for the catalytic mechanism and fatty acid transport.
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Authors
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G.Jogl,
L.Tong.
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Ref.
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Cell, 2003,
112,
113-122.
[DOI no: ]
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PubMed id
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Abstract
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Carnitine acyltransferases have crucial roles in the transport of fatty acids
for beta-oxidation. Dysregulation of these enzymes can lead to serious diseases
in humans, and they are targets for therapeutic development against diabetes. We
report the crystal structures of murine carnitine acetyltransferase (CRAT),
alone and in complex with its substrate carnitine or CoA. The structure contains
two domains. Surprisingly, these two domains share the same backbone fold, which
is also similar to that of chloramphenicol acetyltransferase and dihydrolipoyl
transacetylase. The active site is located at the interface between the two
domains. Carnitine and CoA are bound in deep channels in the enzyme, on opposite
sides of the catalytic His343 residue. The structural information provides a
molecular basis for understanding the catalysis by carnitine acyltransferases
and for designing their inhibitors. Specifically, our structural information
suggests that the substrate carnitine may assist the catalysis by stabilizing
the oxyanion in the reaction intermediate.
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Figure 4.
Figure 4. The CoA Binding Site of CRAT(A) Final
2F[o]–F[c] electron density map for CoA at 2.3 Å
resolution. The contour level is at 1σ. Produced with Setor
(Evans, 1993).(B) Stereo diagram showing the CoA binding site of
CRAT. The CoA molecule is shown in brown. Produced with
Ribbons (Carson, 1987).(C) Overlap of the binding modes of CoA
to CRAT (in brown) and CAT (in cyan).(D) Molecular surface of
CRAT in the region of the CoA binding site. (C and D) produced
with Grasp (Nicholls et al., 1991).
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Figure 6.
Figure 6. The Catalytic Mechanism of Carnitine
AcyltransferasesThe catalytic His343 residue can extract the
proton from either carnitine or CoA. The oxyanion in the
tetrahedral intermediate is stabilized by interactions with
carnitine and the side chain hydroxyl of Ser554.
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The above figures are
reprinted
by permission from Cell Press:
Cell
(2003,
112,
113-122)
copyright 2003.
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