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首页> 外文期刊>Journal of Molecular Biology >Crystal structure of fully ligated adenylosuccinate synthetase from Plasmodium falciparum.
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Crystal structure of fully ligated adenylosuccinate synthetase from Plasmodium falciparum.

机译：恶性疟原虫完全连接的腺苷琥珀酸合成酶的晶体结构。

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摘要

In the absence of the de novo purine nucleotide biosynthetic pathway in parasitic protozoa, purine salvage is of primary importance for parasite survival. Enzymes of the salvage pathway are, therefore, good targets for anti-parasitic drugs. Adenylosuccinate synthetase (AdSS), catalysing the first committed step in the synthesis of AMP from IMP, is a potential target for anti-protozoal chemotherapy. We report here the crystal structure of adenylosuccinate synthetase from the malaria parasite, Plasmodium falciparum, complexed to 6-phosphoryl IMP, GDP, Mg2+ and the aspartate analogue, hadacidin at 2 A resolution. The overall architecture of P. falciparum AdSS (PfAdSS) is similar to the known structures from Escherichia coli, mouse and plants. Differences in substrate interactions seen in this structure provide a plausible explanation for the kinetic differences between PfAdSS and the enzyme from other species. Additional hydrogen bonding interactions of the protein with GDP may account for the ordered binding of substrates to the enzyme. The dimer interface of PfAdSS is also different, with a pronounced excess of positively charged residues. Differences highlighted here provide a basis for the design of species-specific inhibitors of the enzyme.
机译：在没有寄生虫原生动物的从头嘌呤核苷酸生物合成途径的情况下，挽救嘌呤对于寄生虫的生存至关重要。因此，挽救途径的酶是抗寄生虫药物的良好靶标。腺苷琥珀酸合成酶（AdSS）催化从IMP合成AMP的第一个重要步骤，是抗原虫化学疗法的潜在目标。我们在这里报告了疟疾寄生虫恶性疟原虫的腺苷琥珀酸合成酶的晶体结构，该晶体结构与6-磷酸IMP，GDP，Mg2 +和天冬氨酸类似物hadacidin在2 A分辨率下复合。恶性疟原虫AdSS（PfAdSS）的总体结构类似于大肠杆菌，小鼠和植物的已知结构。在此结构中看到的底物相互作用的差异为PfAdSS与其他物种的酶之间的动力学差异提供了合理的解释。蛋白质与GDP的其他氢键相互作用可能解释了底物与酶的有序结合。 PfAdSS的二聚体界面也不同，带有明显过量的带正电残基。这里强调的差异为酶的物种特异性抑制剂的设计提供了基础。

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