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首页> 外文期刊>Nature structural biology >Insights into antifolate resistance from malarial DHFR-TS structures
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Insights into antifolate resistance from malarial DHFR-TS structures

机译：从疟疾DHFR-TS结构了解抗叶酸能力

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Plasmodium falciparum dihydrofolate reductase-thymidylate synthase (PfDHFR-TS) is an important target of antimalarial drugs. The efficacy of this class of DHFR-inhibitor drugs is now compromised because of mutations that prevent drug binding yet retain enzyme activity. The crystal structures of PfDHFR-TS from the wild type (TM4/8.2) and the quadruple drug-resistant mutant (V1/S) strains, in complex with a potent inhibitor WR99210, as well as the resistant double mutant (K1 CB1) with the antimalarial pyrimethamine, reveal features for overcoming resistance. In contrast to pyrimethamine, the flexible side chain of WR99210 can adopt a conformation that fits well in the active site, thereby contributing to binding. The single-chain bifunctional PfDHFR-TS has a helical insert between the DHFR and TS domains that is involved in dimerization and domain organization. Moreover, positively charged grooves on the surface of the dimer suggest a function in channeling of substrate from TS to DHFR active sites. These features provide possible approaches for the design of new drugs to overcome antifolate resistance. [References: 57]
机译：恶性疟原虫二氢叶酸还原酶-胸苷酸合酶（PfDHFR-TS）是抗疟药物的重要靶标。这类DHFR抑制剂药物的功效现在受到损害，因为它阻止了药物结合，但保留了酶的活性。来自野生型（TM4 / 8.2）和四重耐药突变株（V1 / S）的PfDHFR-TS的晶体结构，与有效的抑制剂WR99210以及耐药双重突变株（K1 CB1）形成复合体抗疟药乙胺嘧啶具有克服耐药性的功能。与乙胺嘧啶相反，WR99210的柔性侧链可以采用一个非常适合活性位点的构象，从而有助于结合。单链双功能PfDHFR-TS在DHFR和TS结构域之间有一个螺旋插入物，参与了二聚化和结构域组织。此外，二聚体表面上带正电荷的凹槽表明底物从TS到DHFR活性位点的通道化。这些特征为克服抗叶酸药物的新药设计提供了可能的方法。 [参考：57]

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