2can
From Proteopedia
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'''HUMAN ORNITHINE AMINOTRANSFERASE COMPLEXED WITH L-CANALINE''' | '''HUMAN ORNITHINE AMINOTRANSFERASE COMPLEXED WITH L-CANALINE''' | ||
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[[Category: Shah, S A.]] | [[Category: Shah, S A.]] | ||
[[Category: Shen, B W.]] | [[Category: Shen, B W.]] | ||
| - | [[Category: | + | [[Category: Ornithine aminotransferase]] |
| - | [[Category: | + | [[Category: Pyridoxal-5'-phosphate]] |
| - | [[Category: | + | [[Category: Transferase]] |
| - | [[Category: | + | [[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 | + | |
Revision as of 18:35, 3 May 2008
HUMAN ORNITHINE AMINOTRANSFERASE COMPLEXED WITH L-CANALINE
Overview
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.
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 Sat May 3 21:35:24 2008
