从恶性疟原虫Triosephosphate异构酶:晶体结构提供了洞察抗疟药物设计。
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Velanker党卫军,Ray党卫军Gokhale RS, Suma年代,巴拉罗姆H,巴拉罗姆P,没吃
从恶性疟原虫Triosephosphate异构酶:晶体结构提供了洞察抗疟药物设计。
结构。1997年6月15日;5 (6):751 - 61。
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9261072 (在PubMed]
- 文摘
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背景:疟疾寄生虫造成的恶性疟原虫是一个重大的公共卫生问题。这种寄生虫缺乏功能性三羧酸循环,使糖酵解唯一的能量来源。尽管寄生虫酶被认为是潜在的抗疟药物靶点,对结构生物学。这里我们报告triosephosphate异构酶的晶体结构(TIM)恶性疟原虫在2.2一项决议。结果:恶性疟原虫蒂姆的晶体结构(PfTIM),大肠杆菌中表达,是由分子置换法使用trypanosomal蒂姆开始模型的结构。蒂姆PfTIM结构的比较与其他结构,尤其是人类蒂姆,显示一些差异。在大多数商旅残留在183是一个谷氨酸但PfTIM亮氨酸。这个亮氨酸残基是完全暴露,连同周围的带正电的补丁,可以负责绑定蒂姆红血球膜。另一个有趣的特性是发生二聚体界面的半胱氨酸残基PfTIM (Cys13),与人类蒂姆这个残渣是蛋氨酸。最后,剩余的96人类蒂姆(Ser96),发生在活性部位附近,苯丙氨酸在PfTIM所取代。 CONCLUSIONS: Although the human and Plasmodium enzymes share 42% amino acid sequence identity, several key differences suggest that PfTIM may turn out to be a potential drug target. We have identified a region which may be responsible for binding PfTIM to cytoskeletal elements or the band 3 protein of erythrocytes; attachment to the erythrocyte membrane may subsequently lead to the extracellular exposure of parts of the protein. This feature may be important in view of a recent report that patients suffering from P. falciparum malaria mount an antibody response to TIM leading to prolonged hemolysis. A second approach to drug design may be provided by the mutation of the largely conserved residue (Ser96) to phenylalanine in PfTIM. This difference may be of importance in designing specific active-site inhibitors against the enzyme. Finally, specific inhibition of PfTIM subunit assembly might be possible by targeting Cys13 at the dimer interface. The crystal structure of PfTIM provides a framework for new therapeutic leads.