Crystal structure of Schistosoma mansoni arginase, a potential drug target for the treatment of schistosomiasis.
Crystal structure of Schistosoma mansoni arginase, a potential drug target for the treatment of schistosomiasis.
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DOI：
10.1021/bi5004519
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发表时间：
2014-07-22
期刊：
影响因子：
2.9
通讯作者：
Christianson DW
中科院分区：
文献类型：
--
作者：
Hai Y;Edwards JE;Van Zandt MC;Hoffmann KF;Christianson DW
在原子分辨率下测定了曼氏血吸虫精氨酸酶（SmARG）的x射线晶体结构及其与几种氨基酸抑制剂配合物的结构。SmARG是一种双核锰金属酶，可催化l-精氨酸水解形成l-鸟氨酸和尿素，该酶在与人类宿主相互作用的所有形式的寄生虫中都被上调。目前的假设表明，寄生精氨酸酶可能通过消耗底物l-精氨酸池在宿主免疫逃避中发挥作用，否则这些底物l-精氨酸将用于免疫应答中的NO生物合成和NO依赖过程。虽然SmARG的氨基酸序列与人类精氨酸酶I只有42%的相同，但对底物结合和催化重要的残基是严格保守的。一般来说，经典的氨基酸抑制剂如2(S)-氨基-6-硼己酸（ABH）与SmARG的结合比与人精氨酸酶I的结合更弱，尽管每个酶活性位点的抑制剂结合模式相同。在酶表面发现了一个能够容纳α，α-二取代氨基酸抑制剂的额外c - α取代基的斑块，这表明这种抑制剂可能具有更高的亲和力和生物活性。本文介绍了SmARG与两种不同的α、α-二取代ABH衍生物络合的结构，并为该方法在增强酶抑制剂亲和力方面提供了概念证明。
The X-ray crystal structure of arginase from Schistosoma mansoni (SmARG) and the structures of its complexes with several amino acid inhibitors have been determined at atomic resolution. SmARG is a binuclear manganese metalloenzyme that catalyzes the hydrolysis of l-arginine to form l-ornithine and urea, and this enzyme is upregulated in all forms of the parasite that interact with the human host. Current hypotheses suggest that parasitic arginases could play a role in host immune evasion by depleting pools of substrate l-arginine that would otherwise be utilized for NO biosynthesis and NO-dependent processes in the immune response. Although the amino acid sequence of SmARG is only 42% identical with that of human arginase I, residues important for substrate binding and catalysis are strictly conserved. In general, classical amino acid inhibitors such as 2(S)-amino-6-boronohexanoic acid (ABH) tend to bind more weakly to SmARG than to human arginase I despite identical inhibitor binding modes in each enzyme active site. The identification of a patch on the enzyme surface capable of accommodating the additional Cα substitutent of an α,α-disubstituted amino acid inhibitor suggests that such inhibitors could exhibit higher affinity and biological activity. The structures of SmARG complexed with two different α,α-disubstituted derivatives of ABH are presented and provide a proof of concept for this approach in the enhancement of enzyme–inhibitor affinity.
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影响因子：
3.9
作者：
Di Costanzo, Luigi;Ilies, Monica;Thorn, Katherine J.;Christianson, David W.
通讯作者：
Christianson, David W.
影响因子：
2.7
作者：
Golebiowski, Adam;Whitehouse, Darren;Schroeter, Hagen
通讯作者：
Schroeter, Hagen
影响因子：
15
作者：
Baggio, R;Elbaum, D;Christianson, DW
通讯作者：
Christianson, DW
DOI：
10.1016/s0969-2126(99)80056-2
发表时间：
1999-04-15
期刊：
STRUCTURE WITH FOLDING & DESIGN
影响因子：
--
作者：
Bewley, MC;Jeffrey, PD;Baker, EN
通讯作者：
Baker, EN
影响因子：
15
作者：
Custot, J;Moali, C;Zimmermann, JL
通讯作者：
Zimmermann, JL