Structure and inhibition of plasmepsin II, a hemoglobin-degrading enzyme from Plasmodium falciparum
Structure and inhibition of plasmepsin II, a hemoglobin-degrading enzyme from Plasmodium falciparum
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DOI：
10.1073/pnas.93.19.10034
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发表时间：
1996-09-17
影响因子：
11.1
通讯作者：
Erickson, JW
中科院分区：
文献类型：
--
作者：
Silva, AM;Lee, AY;Erickson, JW
恶性疟原虫是疟疾的主要病原体，疟疾是一种全球性的重要疾病，对氯喹和甲氟喹等现有药物的耐药性正在以惊人的速度蔓延，我们的抗疟药物几乎耗尽。疟疾寄生虫编码两种同源天冬氨酸蛋白酶，即血浆蛋白酶I和II，它们是其重要组成部分。 我们确定了重组血浆蛋白酶 II 与胃酶抑素 A 复合物的晶体结构。这是首次报道的恶性疟原虫蛋白的晶体结构。这些晶体含有两种不同构象的分子，揭示了酶的显着程度的域间灵活性。该结构被用来设计一系列选择性低分子量化合物，抑制血浆蛋白酶 II 和培养物中恶性疟原虫的生长。
Plasmodium falciparum is the major causative agent of malaria, a disease of worldwide importance, Resistance to current drugs such as chloroquine and mefloquine is spreading at an alarming rate, and our antimalarial armamentarium is almost depleted, The malarial parasite encodes two homologous aspartic proteases, plasmepsins I and II, which are essential components of its hemoglobin-degradation pathway and are novel targets for antimalarial drug development, We have determined the crystal structure of recombinant plasmepsin II complexed with pepstatin A. This represents the first reported crystal structure of a protein from P. falciparum. The crystals contain molecules in two different conformations, revealing a remarkable degree of interdomain flexibility of the enzyme. The structure was used to design a series of selective low molecular weight compounds that inhibit both plasmepsin II and the growth of P. falciparum in culture.