Full-length Plasmodium falciparum myosin A and essential light chain PfELC structures provide new anti-malarial targets.
Full-length Plasmodium falciparum myosin A and essential light chain PfELC structures provide new anti-malarial targets.
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全长恶性疟原虫肌球蛋白A和必需的轻链PfELC结构提供了新的抗疟疾靶点。
DOI：
10.7554/elife.60581
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发表时间：
2020-10-13
期刊：
影响因子：
7.7
通讯作者：
Houdusse A
中科院分区：
文献类型：
--
作者：
Moussaoui D;Robblee JP;Auguin D;Krementsova EB;Haase S;Blake TCA;Baum J;Robert-Paganin J;Trybus KM;Houdusse A
疟原虫属的寄生虫是疟疾的病原体。恶性疟原虫的移动性、感染性和最终的致病性依赖于一种称为滑动体的大分子复合物。在滑体的核心是一个必要的和分歧肌球蛋白A马达（PfMyoA），一个一级药物靶点抗疟疾。在这里，我们提出了全长结构的PfMyoA在其摩托车的两个国家。我们报告了新的相互作用，是必不可少的电机启动和模式的识别其两个轻链（PfELC和MTIP）由两个简并IQ图案。使用PfMyoA变体的动力学和运动性测定，沿着分子动力学，展示了特异性引发和非典型序列适应如何调节马达的机械化学性质。PfELC在疟疾发病机制中的重要作用的证据的支持下，这些结构提供了一个蓝图，为未来的抗疟疾药物的设计，靶向滑体电机及其调控元件。
Parasites from the genus Plasmodium are the causative agents of malaria. The mobility, infectivity, and ultimately pathogenesis of Plasmodium falciparum rely on a macromolecular complex, called the glideosome. At the core of the glideosome is an essential and divergent Myosin A motor (PfMyoA), a first order drug target against malaria. Here, we present the full-length structure of PfMyoA in two states of its motor cycle. We report novel interactions that are essential for motor priming and the mode of recognition of its two light chains (PfELC and MTIP) by two degenerate IQ motifs. Kinetic and motility assays using PfMyoA variants, along with molecular dynamics, demonstrate how specific priming and atypical sequence adaptations tune the motor’s mechano-chemical properties. Supported by evidence for an essential role of the PfELC in malaria pathogenesis, these structures provide a blueprint for the design of future anti-malarials targeting both the glideosome motor and its regulatory elements.