Refined 1.8 A structure of human aldose reductase complexed with the potent inhibitor zopolrestat.
Refined 1.8 A structure of human aldose reductase complexed with the potent inhibitor zopolrestat.
复制标题
精制 1.8 人醛糖还原酶与强效抑制剂佐波尔司他复合的结构。
DOI：
10.1073/pnas.90.21.9847
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发表时间：
1993
影响因子：
11.1
通讯作者：
Quiocho,FA
中科院分区：
文献类型：
--
作者：
Wilson,DK;Tarle,I;Petrash,JM;Quiocho,FA
由于醛糖还原酶（EC 1.1.1.21）的作用被认为与影响神经、肾和视觉系统的糖尿病并发症的发病机制有关，因此治疗剂的开发吸引了大量的努力。我们报告了完善的1.8 A的X-射线结构的人全酶与佐泊司他，最有效的非竞争性抑制剂之一。佐泊司他紧贴在疏水性活性位点口袋中，并诱导两个肽段的铰链瓣运动，从而关闭口袋。通过与15个残基（10个疏水残基）、13个与NADPH辅酶和9个与4个水分子形成110个接触（≤ 4 A），在抑制剂结合上实现了优异的互补性和亲和力。结构是理解这类抑制剂的作用模式和合理设计更好的治疗方法的关键。
As the action of aldose reductase (EC 1.1.1.21) is believed to be linked to the pathogenesis of diabetic complications affecting the nervous, renal, and visual systems, the development of therapeutic agents has attracted intense effort. We report the refined 1.8 A x-ray structure of the human holoenzyme complexed with zopolrestat, one of the most potent noncompetitive inhibitors. The zopolrestat fits snugly in the hydrophobic active site pocket and induces a hinge-flap motion of two peptide segments that closes the pocket. Excellent complementarity and affinity are achieved on inhibitor binding by the formation of 110 contacts (< or = 4 A) with 15 residues (10 hydrophobic), 13 with the NADPH coenzyme and 9 with four water molecules. The structure is key to understanding the mode of action of this class of inhibitors and for rational design of better therapeutics.