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1gbn

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{{STRUCTURE_1gbn| PDB=1gbn | SCENE= }}
{{STRUCTURE_1gbn| PDB=1gbn | SCENE= }}
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'''HUMAN ORNITHINE AMINOTRANSFERASE COMPLEXED WITH THE NEUROTOXIN GABACULINE'''
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===HUMAN ORNITHINE AMINOTRANSFERASE COMPLEXED WITH THE NEUROTOXIN GABACULINE===
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==Overview==
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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--&gt;His and Arg180--&gt;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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{{ABSTRACT_PUBMED_9309222}}
==About this Structure==
==About this Structure==
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[[Category: Transferase]]
[[Category: Transferase]]
[[Category: Urea cycle]]
[[Category: Urea cycle]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Tue Jul 1 05:02:29 2008''

Revision as of 02:02, 1 July 2008

Image:1gbn.png

Template:STRUCTURE 1gbn

HUMAN ORNITHINE AMINOTRANSFERASE COMPLEXED WITH THE NEUROTOXIN GABACULINE

Template:ABSTRACT PUBMED 9309222

About this Structure

1GBN is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.

Reference

Human ornithine aminotransferase complexed with L-canaline and gabaculine: structural basis for substrate recognition., Shah SA, Shen BW, Brunger AT, Structure. 1997 Aug 15;5(8):1067-75. PMID:9309222

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