STRUCTURAL-ANALYSIS OF HUMAN ALPHA-CLASS GLUTATHIONE TRANSFERASE A1-1 IN THE APO-FORM AND IN COMPLEXES WITH ETHACRYNIC-ACID AND ITS GLUTATHIONE CONJUGATE
STRUCTURAL-ANALYSIS OF HUMAN ALPHA-CLASS GLUTATHIONE TRANSFERASE A1-1 IN THE APO-FORM AND IN COMPLEXES WITH ETHACRYNIC-ACID AND ITS GLUTATHIONE CONJUGATE
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DOI：
10.1016/s0969-2126(01)00206-4
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发表时间：
1995-07-15
期刊：
影响因子：
5.7
通讯作者：
JONES, TA
中科院分区：
文献类型：
--
作者：
CAMERON, AD;SINNING, I;JONES, TA
背景资料：谷胱甘肽转移酶（GST）是一类催化谷胱甘肽三肽与多种疏水化合物结合的同工酶。最近，一些X-射线结构已被报道，已确定在这些酶的谷胱甘肽和底物结合位点。从哺乳动物来源的谷胱甘肽自由酶的结构还没有，但是，被reportedprevious.Results：我们已经解决了结构的人α-类GST，同工酶A1-1，无论是在unliganded形式和复合物的抑制剂ethacrynic酸和谷胱甘肽共轭。这些结构已经分别被细化到2.5埃、2.7埃和2.0埃的分辨率。这两种形式的抑制剂都清楚地存在于相关的electron density.Conclusions：这里报道的三种结构之间的主要差异涉及C-末端α-螺旋，这是一个特性的α-类酶。当疏水底物结合位点（H-位点）被占据时，该螺旋在活性位点上形成盖子，但否则它是无序的。在没有辅酶谷胱甘肽的情况下，依他尼酸似乎以非生产性模式结合。
Background: Glutathione transferases (GSTs) constitute a family of isoenzymes that catalyze the conjugation of the tripeptide glutathione with a wide variety of hydrophobic compounds bearing an electrophilic functional group. Recently, a number of X-ray structures have been reported which have defined both the glutathione- and the substrate-binding sites in these enzymes. The structure of the glutathione-free enzyme from a mammalian source has not, however, been reported previously.Results: We have solved structures of a human alpha-class GST, isoenzyme A1-1, both in the unliganded form and in complexes with the inhibitor ethacrynic acid and its glutathione conjugate. These structures have been refined to resolutions of 2.5 Angstrom, 2.7 Angstrom and 2.0 Angstrom respectively. Both forms of the inhibitor are clearly present in the associated electron density.Conclusions: The major differences among the three structures reported here involve the C-terminal alpha-helix, which is a characteristic of the alpha-class enzyme. This helix forms a lid over the active site when the hydrophobic substrate binding site (H-site) is occupied but it is otherwise disordered. Ethacrynic acid appears to bind in a non-productive mode in the absence of the coenzyme glutathione.