Structures of the Plasmodium falciparum heat-shock protein 70-x ATPase domain in complex with chemical fragments identify conserved and unique binding sites.
Structures of the Plasmodium falciparum heat-shock protein 70-x ATPase domain in complex with chemical fragments identify conserved and unique binding sites.
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DOI：
10.1107/s2053230x21007378
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发表时间：
2021-08-01
期刊：
影响因子：
--
通讯作者：
Vakonakis I
中科院分区：
文献类型：
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作者：
Mohamad N;O'Donoghue A;Kantsadi AL;Vakonakis I
从疟原虫恶性疟原虫中筛选了233个化学片段，以结合Hsp70-x伴侣蛋白的atp酶结构域。该结构域与不同片段的复合物的晶体结构揭示了atp酶催化袋附近的主要结合位点。结果表明，该结合位点附近的残基在恶性疟原虫和人红细胞Hsp70伴侣蛋白之间不保守，这可能为特异性抑制疟原虫酶提供了基础。恶性疟原虫侵入红细胞，并以一种增加这种疟疾寄生虫毒力的方式对红细胞进行广泛修饰。一种单一的热休克70 kda型伴侣蛋白PfHsp70-x是输出到宿主细胞的寄生虫蛋白之一。PfHsp70-x协助形成一种关键蛋白复合物，该蛋白复合物支持寄生虫的毒力并支持寄生虫在发热期的生长。先前的工作解决了PfHsp70-x atp酶和底物结合域的晶体结构，并表明它们与人类的对应物高度相似。在这里，筛选了233个化学片段结合到PfHsp70-x atp酶结构域，得到了该结构域与配体复合物的三种晶体结构。确定了两个结合位点，大多数配体结合在atp酶核苷酸结合袋附近。虽然参与直接配体相互作用的氨基酸在寄生虫和人红细胞伴侣之间是保守的，但在配体附近也存在一个非保守残基。这项工作表明，PfHsp70-x具有可以被小分子配体利用的结合位点，可以特异性抑制寄生虫伴侣蛋白。
233 chemical fragments were screened for binding to the ATPase domain of the Hsp70-x chaperone from the malaria parasite Plasmodium falciparum. Crystallographic structures of this domain in complex with different fragments revealed a major binding site proximal to the ATPase catalytic pocket. It is shown that a residue near this binding site is not conserved between P. falciparum and human erythrocytic Hsp70 chaperones, which may provide a basis for specific inhibition of the parasite enzyme. Plasmodium falciparum invades erythrocytes and extensively modifies them in a manner that increases the virulence of this malaria parasite. A single heat-shock 70 kDa-type chaperone, PfHsp70-x, is among the parasite proteins exported to the host cell. PfHsp70-x assists in the formation of a key protein complex that underpins parasite virulence and supports parasite growth during febrile episodes. Previous work resolved the crystallographic structures of the PfHsp70-x ATPase and substrate-binding domains, and showed them to be highly similar to those of their human counterparts. Here, 233 chemical fragments were screened for binding to the PfHsp70-x ATPase domain, resulting in three crystallographic structures of this domain in complex with ligands. Two binding sites were identified, with most ligands binding proximal to the ATPase nucleotide-binding pocket. Although amino acids participating in direct ligand interactions are conserved between the parasite and human erythrocytic chaperones, one nonconserved residue is also present near the ligand. This work suggests that PfHsp70-x features binding sites that may be exploitable by small-molecule ligands towards the specific inhibition of the parasite chaperone.