2can
From Proteopedia
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HUMAN ORNITHINE AMINOTRANSFERASE COMPLEXED WITH L-CANALINE
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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 with CAN as ligand. Active as Ornithine aminotransferase, with EC number 2.6.1.13 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 Mon Nov 12 21:13:22 2007
