2can
From Proteopedia
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| , resolution 2.30Å | |||||||
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| Ligands: | |||||||
| Activity: | Ornithine aminotransferase, with EC number 2.6.1.13 | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
HUMAN ORNITHINE AMINOTRANSFERASE COMPLEXED WITH L-CANALINE
Contents |
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.
Disease
Known disease associated with this structure: Gyrate atrophy of choroid and retina with ornithinemia, B6 responsive or unresponsive OMIM:[258870]
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 Thu Mar 20 16:13:06 2008
