Structures of plasmepsin II from Plasmodium falciparum in complex with two hydroxyethylamine-based inhibitors
Structures of plasmepsin II from Plasmodium falciparum in complex with two hydroxyethylamine-based inhibitors
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DOI：
10.1107/s2053230x15022049
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发表时间：
2015-12-01
影响因子：
0.9
通讯作者：
Tars, Kaspars
中科院分区：
文献类型：
--
作者：
Recacha, Rosario;Leitans, Janis;Tars, Kaspars
Plasmepsin II （PMII）是恶性疟原虫基因组中发现的10种Plasmepsin （PMs）之一，恶性疟原虫是最严重和最致命的疟疾形式的病原体。由于出现了对氯喹和磺胺多辛/乙胺嘧啶等现有抗疟药具有耐药性的恶性疟原虫菌株，因此不断面临着寻找新的和持久的化疗药物疗法的压力。此前，已有文献报道了PMII与NU655（一种有效的抗疟疾羟乙胺抑制剂）配合物的晶体结构，以及在其基础上设计的新化合物。在本研究中，新设计的两种羟乙胺类抑制剂PG418和PG394与PMII共结晶，并与PMII- nu655配合物的结构进行了解析、分析和比较。对PMII-PG418复合物的结构分析表明，flap环可以采用完全封闭的构象，通过与抑制剂的相互作用来稳定，也可以采用完全开放的构象，导致活性位点空腔的整体膨胀，从而导致抑制剂的不稳定结合。PG418还稳定了PMII不对称单元中另一个单体的柔性环Gln275-Met286，该环在PMII- nu655复合物结构中无序。PMII与抑制剂PG418配合物的晶体结构显示了血浆蛋白酶活性位点腔的构象灵活性。在设计新的强效plasmepsin抑制剂时，必须考虑PG418和PG394 P1 '位置的不同片段与Thr217的相互作用。
Plasmepsin II (PMII) is one of the ten plasmepsins (PMs) identified in the genome of Plasmodium falciparum, the causative agent of the most severe and deadliest form of malaria. Owing to the emergence of P. falciparum strains that are resistant to current antimalarial agents such as chloroquine and sulfadoxine/pyrimethamine, there is a constant pressure to find new and lasting chemotherapeutic drug therapies. Previously, the crystal structure of PMII in complex with NU655, a potent antimalarial hydroxyethylamine-based inhibitor, and the design of new compounds based on it have been reported. In the current study, two of these newly designed hydroxyethylamine-based inhibitors, PG418 and PG394, were cocrystallized with PMII and their structures were solved, analyzed and compared with that of the PMII-NU655 complex. Structural analysis of the PMII-PG418 complex revealed that the flap loop can adopt a fully closed conformation, stabilized by interactions with the inhibitor, and a fully open conformation, causing an overall expansion in the active-site cavity, which in turn causes unstable binding of the inhibitor. PG418 also stabilizes the flexible loop Gln275-Met286 of another monomer in the asymmetric unit of PMII, which is disordered in the PMII-NU655 complex structure. The crystal structure of PMII in complex with the inhibitor PG418 demonstrates the conformational flexibility of the active-site cavity of the plasmepsins. The interactions of the different moieties in the P1 ' position of PG418 and PG394 with Thr217 have to be taken into account in the design of new potent plasmepsin inhibitors.