X-ray structure of trypanothione reductase from Crithidia fasciculata at 2.4-A resolution.
X-ray structure of trypanothione reductase from Crithidia fasciculata at 2.4-A resolution.
复制标题
来自 Crithidia fasciculata 的锥硫酮还原酶的 X 射线结构，分辨率为 2.4-A。
DOI：
10.1073/pnas.88.19.8764
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发表时间：
1991
影响因子：
11.1
通讯作者：
Henderson,GB
中科院分区：
文献类型：
--
作者：
Kuriyan,J;Kong,XP;Krishna,TS;Sweet,RM;Murgolo,NJ;Field,H;Cerami,A;Henderson,GB
锥虫和相关的原生动物寄生虫缺乏谷胱甘肽还原酶，而具有一种密切相关的酶，作为谷胱甘肽-精子缀合物，锥虫硫酮的还原剂。人类和寄生虫酶具有互斥的底物特异性，这为通过特异性抑制寄生虫酶来设计治疗剂提供了途径。本文报道了束状棘豆中锥虫硫肽还原酶的三维结构，并表明其与人类谷胱甘肽还原酶的结构非常相似。特别是，在两种酶中，围绕催化机制的核心结构几乎相同。然而，在底物结合位点上发现了显著的差异。谷胱甘肽还原酶中的一簇碱性残基被锥虫硫肽还原酶中的中性、疏水性或酸性残基所取代，这与亚精胺键的性质和底物从{-}2到+1的总电荷变化相一致。锥虫硫酮还原酶的结合位点更开放，因为在位点上形成的结构域旋转了约4{度}，残基的相对位移高达2-3{埃}，可以与潜在的抑制剂相互作用，并补充了先前对这两种酶的建模和诱变研究。
Trypanosomes and related protozoan parasites lack glutathione reductase and possess instead a closely related enzyme that serves as the reductant of a bis(glutathione)-spermidien conjugate, trypanothione. The human and parasite enzymes have mutually exclusive substrate specificities, providing a route for the design of therapeutic agents by specific inhibition of the parasite enzyme. The authors report here the three-dimensional structure of trypanothione reductase from Crithidia fasciculata and show that it closely resembles the structure of human glutathione reductase. In particular, the core structure surrounding the catalytic machinery is almost identical in the two enzymes. However, significant differences are found at the substrate binding sites. A cluster of basic residues in glutathione reductase is replaced by neutral, hydrophobic, or acidic residues in trypanothione reductase, consistent with the nature of the spermidine linkage and the change in overall charge of the substrate from {minus}2 to +1, respectively. The binding site is more open in trypanothione reductase due to rotations of about 4{degree} in the domains that form in site, with relative shifts of as much as 2-3 {angstrom} in residues that can interact with potential inhibitors and complement previous modeling and mutagenesis studies on the two enzymes.