Structural Motility, Institut Curie, Université Paris Sciences et Lettres, Sorbonne Université, CNRS UMR144, 75248, Paris, France.
Structural Biology group, European Synchrotron Radiation Facility (ESRF), 71, Avenue des Martyrs, 38000, Grenoble, France.
Nat Commun. 2023 Jun 12;14(1):3463. doi: 10.1038/s41467-023-38976-7.
Malaria results in more than 500,000 deaths per year and the causative Plasmodium parasites continue to develop resistance to all known agents, including different antimalarial combinations. The class XIV myosin motor PfMyoA is part of a core macromolecular complex called the glideosome, essential for Plasmodium parasite mobility and therefore an attractive drug target. Here, we characterize the interaction of a small molecule (KNX-002) with PfMyoA. KNX-002 inhibits PfMyoA ATPase activity in vitro and blocks asexual blood stage growth of merozoites, one of three motile Plasmodium life-cycle stages. Combining biochemical assays and X-ray crystallography, we demonstrate that KNX-002 inhibits PfMyoA using a previously undescribed binding mode, sequestering it in a post-rigor state detached from actin. KNX-002 binding prevents efficient ATP hydrolysis and priming of the lever arm, thus inhibiting motor activity. This small-molecule inhibitor of PfMyoA paves the way for the development of alternative antimalarial treatments.
疟疾每年导致超过 50 万人死亡，而引起疟疾的疟原虫继续对所有已知的药物产生抗药性，包括不同的抗疟组合。XIV 类肌球蛋白马达 PfMyoA 是称为滑行车的核心大分子复合物的一部分，对疟原虫的运动至关重要，因此是一个有吸引力的药物靶点。在这里，我们描述了小分子 (KNX-002) 与 PfMyoA 的相互作用。KNX-002 在体外抑制 PfMyoA 的 ATP 酶活性，并阻断裂殖子的无性血期生长，裂殖子是三种运动性疟原虫生命周期阶段之一。通过结合生化测定和 X 射线晶体学，我们证明 KNX-002 使用以前未描述的结合模式抑制 PfMyoA，将其隔离在与肌动蛋白分离的后紧张状态。KNX-002 结合阻止了有效 ATP 水解和杠杆臂的引发，从而抑制了马达活性。这种 PfMyoA 的小分子抑制剂为开发替代抗疟药物铺平了道路。
