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首页> 外文期刊>Acta crystallographica. Section D, Biological crystallography. >Three-dimensional structures of Plasmodium falciparum spermidine synthase with bound inhibitors suggest new strategies for drug design
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Three-dimensional structures of Plasmodium falciparum spermidine synthase with bound inhibitors suggest new strategies for drug design

机译：三维结构的疟原虫恶性疟原虫与绑定亚精胺合成酶抑制剂为药物设计提供新的策略

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摘要

The enzymes of the polyamine-biosynthesis pathway have been proposed to be promising drug targets in the treatment of malaria. Spermidine synthase (SpdS; putrescine aminopropyltransferase) catalyzes the transfer of the aminopropyl moiety from decarboxylated S-adenosylmethionine to putrescine, leading to the formation of spermidine and 50-methylthioadenosine (MTA). In this work, X-ray crystallography was used to examine ligand complexes of SpdS from the malaria parasite Plasmodium falciparum (PfSpdS). Five crystal structures were determined of PfSpdS in complex with MTA and the substrate putrescine, with MTA and spermidine, which was obtained as a result of the enzymatic reaction taking place within the crystals, with dcAdoMet and the inhibitor 4-methylaniline, with MTA and 4-aminomethylaniline, and with a compound predicted in earlier in silico screening to bind to the active site of the enzyme, benzimidazol( 2-yl) pentan-1-amine (BIPA). In contrast to the other inhibitors tested, the complex with BIPA was obtained without any ligand bound to the dcAdoMet-binding site of the enzyme. The complexes with the aniline compounds and BIPA revealed a new mode of ligand binding to PfSpdS. The observed binding mode of the ligands, and the interplay between the two substrate-binding sites and the flexible gatekeeper loop, can be used in the design of new approaches in the search for new inhibitors of SpdS.
机译：polyamine-biosynthesis途径的酶提出了很有前途的药物靶点治疗疟疾。(法拉第笼;催化转移aminopropyl的一部分从脱羧S-adenosylmethionine腐胺,导致的形成亚精胺和50-methylthioadenosine (MTA)。这项工作,利用x射线晶体学检查配体复合物的spd的疟疾寄生虫恶性疟原虫(PfSpdS)。晶体结构测定的PfSpdS复杂与MTA衬底腐胺,MTA和亚精胺,作为获得酶促反应的结果在晶体内,与dcAdoMet抑制剂4-methylaniline, MTA和4-aminomethylaniline,化合物在早些时候预测硅片筛选绑定酶的活性部位,benzimidazol (2-yl) pentan-1-amine (BIPA)。其他抑制剂进行测试,与BIPA复杂没有任何配体结合了dcAdoMet-binding的酶。与苯胺化合物和BIPA复合物揭示PfSpdS配体结合的新模式。观察到的绑定模式的配体,两个substrate-binding网站之间的相互作用和灵活的看门人循环,可以使用在寻找新方法的设计新的抑制剂的spd。

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