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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Crystal structure of dihydrofolate reductase from Plasmodium vivax: Pyrimethamine displacement linked with mutation-induced resistance
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Crystal structure of dihydrofolate reductase from Plasmodium vivax: Pyrimethamine displacement linked with mutation-induced resistance

机译：间日疟原虫二氢叶酸还原酶的晶体结构：乙胺嘧啶置换与突变诱导的抗性相关

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摘要

Pyrimethamine (Pyr) targets dihydrofolate reductase of Plasmodium vivax (PvDHFR) as well as other malarial parasites, but its use as antimalarial is hampered by the widespread high resistance. Comparison of the crystal structures of PvDHFR from wild-type and the Pyr-resistant (SP21, Ser-58 -> Arg + Ser-117 -> Asn) strain as complexes with NADPH and Pyr or its analog lacking p-Cl (Pyr20) clearly shows that the steric conflict arising from the side chain of Asn-117 in the mutant enzyme, accompanied by the loss of binding to Ser-120, is mainly responsible for the reduction in binding of Pyr. Pyr20 still effectively inhibits both the wild-type and SP21 proteins, and the x-ray structures of these complexes show how Pyr20 fits into both active sites without steric strain. These structural insights suggest a general approach for developing new generations of antimalarial DHFR inhibitors that, by only occupying substrate space of the active site, would retain binding affinity with the mutant enzymes.
机译：乙胺嘧啶（Pyr）靶向间日疟原虫（PvDHFR）以及其他疟原虫的二氢叶酸还原酶，但由于其广泛的高耐药性而使其用作抗疟药受到阻碍。与NADPH和Pyr或缺乏p-Cl（Pyr20）的类似物复合的野生型和耐Pyr（SP21，Ser-58-> Arg + Ser-117-> Asn）菌株的PvDHFR的晶体结构比较清楚地表明，突变酶中Asn-117侧链引起的空间冲突，伴随与Ser-120的结合丧失，是造成Pyr结合减少的主要原因。 Pyr20仍然有效抑制野生型和SP21蛋白，这些复合物的X射线结构表明Pyr20如何在没有空间应变的情况下适合两个活性位点。这些结构见解提出了开发新一代抗疟药DHFR抑制剂的通用方法，该方法仅占据活性位点的底物空间即可保持与突变酶的结合亲和力。

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