Structures of Ser205 mutant plasmepsin II from Plasmodium falciparum at 1.8 Å in complex with the inhibitors rs367 and rs370
Structures of Ser205 mutant plasmepsin II from Plasmodium falciparum at 1.8 Å in complex with the inhibitors rs367 and rs370
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DOI：
10.1107/s0907444902014695
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发表时间：
2002-12-01
影响因子：
2.2
通讯作者：
Silva, AM
中科院分区：
文献类型：
--
作者：
Asojo, OA;Afonina, E;Silva, AM
Plasmepsin II是在恶性疟原虫食物液泡中发现的四种具有催化活性的Plasmepsin之一。这些酶通过在Phe33和Leu34之间的α -链上进行切割来启动血红蛋白降解。恶性疟原虫Ser205突变体plasmepsin II与两种抑制剂复合物的晶体结构在空间组I222中以1.8埃的分辨率细化，R因子分别为19.9和19.5%。每个晶体在不对称单元中包含一个单体。这两种抑制剂都有一个ph - leu核心，并结合四面体过渡态模拟羟丙胺。抑制剂rs367在P2位置有2,6-二甲基苯基氧乙酰基，在P2‘位置有3-氨基苯甲酰胺，而rs370在P2’位置有相同的P2基团，但在4-氨基苯甲酰胺。这些配合物揭示了抑制剂与结合腔残基之间的关键保守氢键，特别是与皮瓣残基Val78和Ser79，催化二偶体Asp34和Asp214以及靠近催化二偶体的残基Ser218和Gly36。这些结构还显示出plasmepsin II结合腔的意想不到的构象变化，可能反映了血红蛋白α链的结合模式。
Plasmepsin II is one of the four catalytically active plasmepsins found in the food vacuole of Plasmodium falciparum. These enzymes initiate hemoglobin degradation by cleavage at the alpha-chain between Phe33 and Leu34. The crystal structures of Ser205 mutant plasmepsin II from P. falciparum in complex with two inhibitors have been refined at a resolution of 1.8 Angstrom in the space group I222 and to R factors of 19.9 and 19.5%. Each crystal contains one monomer in the asymmetric unit. Both inhibitors have a Phe-Leu core and incorporate tetrahedral transition-state mimetic hydroxypropylamine. The inhibitor rs367 possesses a 2,6-dimethylphenyloxyacetyl group at the P2 position and 3-aminobenzamide at the P2' position, while rs370 has the same P2 group but 4-aminobenzamide in the P2' position. These complexes reveal key conserved hydrogen bonds between the inhibitor and the binding-cavity residues, notably with the flap residues Val78 and Ser79, the catalytic dyad Asp34 and Asp214 and the residues Ser218 and Gly36 that are in proximity to the catalytic dyad. The structures also show unexpected conformational variability of the binding cavity of plasmepsin II and may reflect the mode of binding of the hemoglobin alpha-chain for cleavage.