3IK7

Human glutathione transferase a4-4 with GSDHN

3IK7 の概要

• エントリーDOI: 10.2210/pdb3ik7/pdb
• 関連するPDBエントリー: 3IK9
• 分子名称: Glutathione S-transferase A4, (S)-2-amino-5-((R)-1-(carboxymethylamino)-3-((3S,4R)-1,4-dihydroxynonan-3-ylthio)-1-oxopropan-2-ylamino)-5-oxopentanoic acid, SULFATE ION, ... (4 entities in total)
• 機能のキーワード: human gst a4-4, enzyme, transferase, cytoplasm, polymorphism
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cytoplasm: O15217
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 104910.69

構造登録者

Balogh, L.M.,Le Trong, I.,Atkins, W.M.,Stenkamp, R.E. (登録日: 2009-08-05, 公開日: 2010-06-23, 最終更新日: 2023-09-06)

主引用文献

Balogh, L.M.,Le Trong, I.,Kripps, K.A.,Shireman, L.M.,Stenkamp, R.E.,Zhang, W.,Mannervik, B.,Atkins, W.M.
Substrate specificity combined with stereopromiscuity in glutathione transferase A4-4-dependent metabolism of 4-hydroxynonenal.
Biochemistry, 49:1541-1548, 2010

PubMed Abstract: Conjugation to glutathione (GSH) by glutathione transferase A4-4 (GSTA4-4) is a major route of elimination for the lipid peroxidation product 4-hydroxynonenal (HNE), a toxic compound that contributes to numerous diseases. Both enantiomers of HNE are presumed to be toxic, and GSTA4-4 has negligible stereoselectivity toward them, despite its high catalytic chemospecificity for alkenals. In contrast to the highly flexible, and substrate promiscuous, GSTA1-1 isoform that has poor catalytic efficiency with HNE, GSTA4-4 has been postulated to be a rigid template that is preorganized for HNE metabolism. However, the combination of high substrate chemoselectivity and low substrate stereoselectivity is intriguing. The mechanism by which GSTA4-4 achieves this combination is important, because it must metabolize both enantiomers of HNE to efficiently detoxify the biologically formed mixture. The crystal structures of GSTA4-4 and an engineered variant of GSTA1-1 with high catalytic efficiency toward HNE, cocrystallized with a GSH-HNE conjugate analogue, demonstrate that GSTA4-4 undergoes no enantiospecific induced fit; instead, the active site residue Arg15 is ideally located to interact with the 4-hydroxyl group of either HNE enantiomer. The results reveal an evolutionary strategy for achieving biologically useful stereopromiscuity toward a toxic racemate, concomitant with high catalytic efficiency and substrate specificity toward an endogenously formed toxin.

PubMed: 20085333
DOI: 10.1021/bi902038u

実験手法

X-RAY DIFFRACTION (1.97 Å)