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PDBsum entry 1gbn
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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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Human ornithine aminotransferase complexed with l-Canaline and gabaculine: structural basis for substrate recognition.
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Authors
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S.A.Shah,
B.W.Shen,
A.T.Brünger.
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Ref.
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Structure, 1997,
5,
1067-1075.
[DOI no: ]
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PubMed id
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Abstract
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BACKGROUND: Ornithine aminotransferase (OAT) is a 45 kDa pyridoxal-5'-phosphate
(PLP)-dependent enzyme that catalyzes the conversion of L-ornithine and
2-oxoglutarate to glutamate-delta-semialdehyde and glutamic acid, respectively.
In humans, loss of OAT function causes an accumulation of ornithine that results
in gyrate atrophy of the choroid and retina, a disease that progressively leads
to blindness. In an effort to learn more about the structural basis of this
enzyme's function, we have determined the X-ray structures of OAT in complex
with two enzyme-activated suicide substrates: L-canaline, an ornithine analog,
and gabaculine, an irreversible inhibitor of several related aminotransferases.
RESULTS: The structures of human OAT bound to the inhibitors gabaculine and
L-canaline were solved to 2.3 A at 110K by difference Fourier techniques. Both
inhibitors coordinate similarly in the active site, binding covalently to the
PLP cofactor and causing a 20 degrees rotation in the cofactor tilt relative to
the ligand-free form. Aromatic-aromatic interactions occur between the bound
gabaculine molecule and active-site residues Tyr85 and Phe177, whereas Tyr55 and
Arg180 provide specific contacts to the alpha-amino and carboxyl groups of
L-canaline. CONCLUSIONS: The OAT-L-canaline complex structure implicates Tyr55
and Arg180 as the residues involved in coordinating with the natural substrate
ornithine during normal enzyme turnover. This correlates well with two
enzyme-inactivating point mutations associated with gyrate atrophy, Tyr55-->His
and Arg180-->Thr. The OAT-gabaculine complex provides the first structural
evidence that the potency of the inhibitor is due to energetically favourable
aromatic interactions with residues in the active site. This aromatic-binding
mode may be relevant to structure-based drug design efforts against other
omega-aminotransferase targets, such as GABA aminotransferase.
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Figure 1.
Figure 1. Substrate and inhibitor chemical structures.
Chemical structures of (a) Image -Ornithine, (b)
a-amino-g-amino-oxybutyric acid ( Image -canaline) and (c)
5-amino-1,3,-cyclohexadienyl carboxylic acid (gabaculine).
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The above figure is
reprinted
by permission from Cell Press:
Structure
(1997,
5,
1067-1075)
copyright 1997.
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