HIGH RESOLUTION CRYSTAL STRUCTURE OF ORNITHINE AMINOTRANSFERASE COMPLEXED WITH THE NEUROTOXIN GABACULINE. Sapan A. Shah, Betty W. Shen and A.T. Brunger. The Howard Hughes Medical Institute and Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520, USA.

Ornithine aminotransferase (OAT) is a 45kD pyridoxal phosphate-dependent enzyme that catalyzes the transfer of the delta amino group of ornithine to an alpha ketoglutarate substrate. OAT and gamma aminobutyric acid transaminase (GABA-AT) belong to the same subgroup of transaminases, and in addition to sharing high sequence homology, are inactivated by common inhibitors. One such inhibitor is the neurotoxin gabaculine (5-amino- 1,3-cyclohexadienylcarboxylic acid), a cyclic analogue of the inhibitory neurotransmitter GABA. We present here a 2.3 angstrom structure of the OAT/gabaculine complex, solved using phases from the native structure (Shen et al, manuscript in preparation). The complex reveals the structural basis for the "suicide" binding of gabaculine to the active site. Gabaculine is positioned in the active site through a hydrogen bond between its carboxyl group and Tyr55. Following binding to the PLP cofactor and aromatization of the cyclohexadienyl ring, the inhibitor is sandwiched in a favorable stacked arrangement between two aromatic residues, Tyr85 and Phe177.