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| - | [[Image:2can.gif|left|200px]] | + | {{Seed}} |
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| | {{STRUCTURE_2can| PDB=2can | SCENE= }} | | {{STRUCTURE_2can| PDB=2can | SCENE= }} |
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| - | '''HUMAN ORNITHINE AMINOTRANSFERASE COMPLEXED WITH L-CANALINE'''
| + | ===HUMAN ORNITHINE AMINOTRANSFERASE COMPLEXED WITH L-CANALINE=== |
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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-->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.
| + | The line below this paragraph, {{ABSTRACT_PUBMED_9309222}}, adds the Publication Abstract to the page |
| | + | (as it appears on PubMed at http://www.pubmed.gov), where 9309222 is the PubMed ID number. |
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| | + | {{ABSTRACT_PUBMED_9309222}} |
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| | ==About this Structure== | | ==About this Structure== |
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| | [[Category: Transferase]] | | [[Category: Transferase]] |
| | [[Category: Urea cycle]] | | [[Category: Urea cycle]] |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 21:35:24 2008'' | + | |
| | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Jul 27 23:26:11 2008'' |
Revision as of 20:26, 27 July 2008
Template:STRUCTURE 2can
HUMAN ORNITHINE AMINOTRANSFERASE COMPLEXED WITH L-CANALINE
Template:ABSTRACT PUBMED 9309222
About this Structure
2CAN 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
Page seeded by OCA on Sun Jul 27 23:26:11 2008
