1OHY

4-AMINOBUTYRATE-AMINOTRANSFERASE inactivated by gamma-ethynyl GABA

1OHY の概要

• エントリーDOI: 10.2210/pdb1ohy/pdb
• 関連するPDBエントリー: 1OHV 1OHW
• 分子名称: 4-AMINOBUTYRATE AMINOTRANSFERASE, PYRIDOXAL-5'-PHOSPHATE, (4E)-4-AMINOHEX-4-ENOIC ACID, ... (5 entities in total)
• 機能のキーワード: transferase, plp-dependent enzyme, aminotransferase, 4- aminobutyric acid, antiepileptic drug target, vigabatrin pyridoxal phosphate, neurotransmitter degradation, mitochondrion, transit peptide
• 由来する生物種: SUS SCROFA (PIG)
• 細胞内の位置: Mitochondrion matrix: P80147
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 215332.82

構造登録者

Storici, P.,Schirmer, T. (登録日: 2003-06-03, 公開日: 2003-10-16, 最終更新日: 2025-04-09)

主引用文献

Storici, P.,De Biase, D.,Bossa, F.,Bruno, S.,Mozzarelli, A.,Peneff, C.,Silverman, R.,Schirmer, T.
Structures of {Gamma}-Aminobutyric Acid (Gaba) Aminotransferase, a Pyridoxal 5'-Phosphate, and [2Fe-2S] Cluster-Containing Enzyme, Complexed with {Gamma}-Ethynyl-Gaba and with the Antiepilepsy Drug Vigabatrin
J.Biol.Chem., 279:363-, 2004

PubMed Abstract: Gamma-aminobutyric acid aminotransferase (GABA-AT) is a pyridoxal 5'-phosphate-dependent enzyme responsible for the degradation of the inhibitory neurotransmitter GABA. GABA-AT is a validated target for antiepilepsy drugs because its selective inhibition raises GABA concentrations in brain. The antiepilepsy drug, gamma-vinyl-GABA (vigabatrin) has been investigated in the past by various biochemical methods and resulted in several proposals for its mechanisms of inactivation. In this study we solved and compared the crystal structures of pig liver GABA-AT in its native form (to 2.3-A resolution) and in complex with vigabatrin as well as with the close analogue gamma-ethynyl-GABA (to 2.3 and 2.8 A, respectively). Both inactivators form a covalent ternary adduct with the active site Lys-329 and the pyridoxal 5'-phosphate (PLP) cofactor. The crystal structures provide direct support for specific inactivation mechanisms proposed earlier on the basis of radio-labeling experiments. The reactivity of GABA-AT crystals with the two GABA analogues was also investigated by polarized absorption microspectrophotometry. The spectral data are discussed in relation to the proposed mechanism. Intriguingly, all three structures revealed a [2Fe-2S] cluster of yet unknown function at the center of the dimeric molecule in the vicinity of the PLP cofactors.

PubMed: 14534310
DOI: 10.1074/JBC.M305884200

実験手法

X-RAY DIFFRACTION (2.8 Å)