Khan Sameena, Sharma Arvind, Belrhali Hassan, Yogavel Manickam, Sharma Amit
Structural and Computational Biology Group, International Centre for Genetic Engineering and Biotechnology (ICGEB), New Delhi, 110067, India.
J Struct Funct Genomics. 2014 Jun;15(2):63-71. doi: 10.1007/s10969-014-9182-1. Epub 2014 Jun 17.
Malaria parasites inevitably develop drug resistance to anti-malarials over time. Hence the immediacy for discovering new chemical scaffolds to include in combination malaria drug therapy. The desirable attributes of new chemotherapeutic agents currently include activity against both liver and blood stage malaria parasites. One such recently discovered compound called cladosporin abrogates parasite growth via inhibition of Plasmodium falciparum lysyl-tRNA synthetase (PfKRS), an enzyme central to protein translation. Here, we present crystal structure of ternary PfKRS-lysine-cladosporin (PfKRS-K-C) complex that reveals cladosporin's remarkable ability to mimic the natural substrate adenosine and thereby colonize PfKRS active site. The isocoumarin fragment of cladosporin sandwiches between critical adenine-recognizing residues while its pyran ring fits snugly in the ribose-recognizing cavity. PfKRS-K-C structure highlights ample space within PfKRS active site for further chemical derivatization of cladosporin. Such derivatives may be useful against additional human pathogens that retain high conservation in cladosporin chelating residues within their lysyl-tRNA synthetase.
随着时间的推移，疟原虫不可避免地会对抗疟药物产生耐药性。因此，迫切需要发现新的化学骨架用于联合疟疾药物治疗。目前新型化学治疗剂的理想特性包括对肝脏和血液阶段疟原虫均有活性。一种最近发现的名为枝孢菌素的化合物通过抑制恶性疟原虫赖氨酰 - tRNA合成酶（PfKRS）来消除寄生虫生长，PfKRS是蛋白质翻译的关键酶。在此，我们展示了三元PfKRS - 赖氨酸 - 枝孢菌素（PfKRS - K - C）复合物的晶体结构，该结构揭示了枝孢菌素模拟天然底物腺苷并由此占据PfKRS活性位点的显著能力。枝孢菌素的异香豆素片段夹在关键的腺嘌呤识别残基之间，而其吡喃环紧密地契合在核糖识别腔内。PfKRS - K - C结构突出了PfKRS活性位点内有足够空间用于枝孢菌素的进一步化学衍生化。此类衍生物可能对其他人类病原体有用，这些病原体在其赖氨酰 - tRNA合成酶中的枝孢菌素螯合残基保持高度保守。
