PDBsum entry 1gbn

Transferase

PDB id: 1gbn

Contents

Protein chain

402 a.a. *

Ligands

GAB-PLP

GBC-PLP ×2

Waters ×329

* Residue conservation analysis

PDB id:

1gbn

Name:

Transferase

Title:

Human ornithine aminotransferase complexed with the neurotoxin gabaculine

Structure:

Ornithine aminotransferase. Chain: a, b, c. Engineered: yes. Other_details: bound inhibitor gabaculine

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562

Biol. unit:

Homo-Tetramer (from PDB file)

Resolution:

2.30Å R-factor: 0.209 R-free: 0.235

Authors:

S.A.Shah,B.W.Shen,A.T.Brunger

Key ref:

S.A.Shah et al. (1997). Human ornithine aminotransferase complexed with L-canaline and gabaculine: structural basis for substrate recognition. Structure, 5, 1067-1075. PubMed id: 9309222 DOI: 10.1016/S0969-2126(97)00258-X

Date:

29-May-97 Release date: 03-Jun-98

Protein chains

P04181  (OAT_HUMAN) -  Ornithine aminotransferase, mitochondrial from Homo sapiens

Seq: 439 a.a.

Struc: 402 a.a.

Enzyme reactions

• Enzyme class: E.C.2.6.1.13 - ornithine aminotransferase.
• Reaction: a 2-oxocarboxylate + L-ornithine = L-glutamate 5-semialdehyde + an L-alpha-amino acid

2-oxocarboxylate + L-ornithine (Bound ligand (Het Group name = GAB) matches with 58.33% similarity) = L-glutamate 5-semialdehyde + L-alpha-amino acid

• Cofactor: Pyridoxal 5'-phosphate

Pyridoxal 5'-phosphate (Bound ligand (Het Group name = PLP) matches with 93.75% similarity)

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1016/S0969-2126(97)00258-X

Structure 5:1067-1075 (1997)

PubMed id: 9309222

Human ornithine aminotransferase complexed with L-canaline and gabaculine: structural basis for substrate recognition.

S.A.Shah, B.W.Shen, A.T.Brünger.

ABSTRACT

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.

Selected figure(s)

Figure 1.
Figure 1. Substrate and inhibitor chemical structures. Chemical structures of (a) Image -Ornithine, (b) a-amino-g-amino-oxybutyric acid ( Image -canaline) and (c) 5-amino-1,3,-cyclohexadienyl carboxylic acid (gabaculine).

The above figure is reprinted by permission from Cell Press: Structure (1997, 5, 1067-1075) copyright 1997.

Figure was selected by an automated process.