Zhang Zhemin, Lyu Meinan, Han Xu, Bandara Sepalika, Cui Meng, Istvan Eva S, Geng Xinran, Tringides Marios L, Gregor William D, Miyagi Masaru, Oberstaller Jenna, Adams John H, Zhang Youwei, Nieman Marvin T, von Lintig Johannes, Goldberg Daniel E, Yu Edward W
Department of Pharmacology, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
Department of Pharmaceutical Sciences, Northeastern University School of Pharmacy, Boston, MA 02115, USA.
Sci Adv. 2024 Dec 20;10(51):eadq6651. doi: 10.1126/sciadv.adq6651. Epub 2024 Dec 18.
Malaria, a devastating parasitic infection, is the leading cause of death in many developing countries. Unfortunately, the most deadliest causative agent of malaria, , has developed resistance to nearly all currently available antimalarial drugs. The Niemann-Pick type C1-related (PfNCR1) transporter has been identified as a druggable target, but its structure and detailed molecular mechanism are not yet available. Here, we present three structures of PfNCR1 with and without the functional inhibitor MMV009108 at resolutions between 2.98 and 3.81 Å using single-particle cryo-electron microscopy (cryo-EM), suggesting that PfNCR1 binds cholesterol and forms a cholesterol transport tunnel to modulate the composition of the parasite plasma membrane. Cholesterol efflux assays show that PfNCR1 is an exporter capable of extruding cholesterol from the membrane. Additionally, the inhibition mechanism of MMV009108 appears to be due to a direct blockage of PfNCR1, preventing this transporter from shuttling cholesterol.
疟疾是一种极具破坏力的寄生虫感染病，是许多发展中国家的主要死因。不幸的是，疟疾最致命的病原体——恶性疟原虫，已对几乎所有目前可用的抗疟药物产生了耐药性。Niemann-Pick C1相关（PfNCR1）转运蛋白已被确定为一个可成药靶点，但其结构和详细分子机制尚不清楚。在此，我们使用单颗粒冷冻电子显微镜（cryo-EM），分别在2.98至3.81 Å的分辨率下，展示了有无功能性抑制剂MMV009108时PfNCR1的三种结构，这表明PfNCR1结合胆固醇并形成一个胆固醇转运通道，以调节寄生虫质膜的组成。胆固醇外排试验表明，PfNCR1是一种能够从膜中排出胆固醇的转运蛋白。此外，MMV009108的抑制机制似乎是由于对PfNCR1的直接阻断，阻止了这种转运蛋白转运胆固醇。
