The intra‐erythrocyte stage of P. falciparum relies primarily on glycolysis to generate adenosine triphosphate (ATP) and the energy required to support growth and reproduction. Lactic acid, a metabolic byproduct of glycolysis, is potentially toxic as it lowers the pH inside the parasite. Plasmodium falciparum formate–nitrite transporter (PfFNT), a 34‐kDa transmembrane protein, has been identified as a novel drug target as it exports lactate from inside the parasite to the surrounding parasitophorous vacuole within the erythrocyte cytosol. The structure and detailed molecular mechanism of this membrane protein are not yet available. Here we present structures of PfFNT in the absence and presence of the functional inhibitor MMV007839 at resolutions of 2.56 Å and 2.78 Å using single‐particle cryo‐electron microscopy. Genetic analysis and transport assay indicate that PfFNT is able to transfer lactate across the membrane. Combined, our data suggest a stepwise displacement mechanism for substrate transport. The PfFNT membrane protein is capable of picking up lactate ions from the parasite’s cytosol, converting them to lactic acids and then exporting these acids into the extracellular space.

中文翻译：

---

恶性疟原虫转运蛋白 PfFNT 转运和抑制的结构基础

恶性疟原虫的红细胞内阶段主要依靠糖酵解产生三磷酸腺苷 (ATP) 和支持生长和繁殖所需的能量。乳酸是糖酵解的代谢副产物，具有潜在的毒性，因为它会降低寄生虫内部的 pH 值。恶性疟原虫 甲酸亚硝酸盐_转运蛋白 (PfFNT) 是一种 34 kDa 的跨膜蛋白，已被确定为一种新的药物靶点，因为它将乳酸从寄生虫内部输出到红细胞胞质溶胶内的周围寄生泡。这种膜蛋白的结构和详细的分子机制尚不清楚。在这里，我们使用单粒子低温电子显微镜以 2.56 Å 和 2.78 Å 的分辨率展示了在不存在和存在功能抑制剂 MMV007839 的情况下 PfFNT 的结构。遗传分析和转运分析表明，PfFNT 能够跨膜转运乳酸。结合起来，我们的数据表明基板传输的逐步位移机制。PfFNT 膜蛋白能够从寄生虫的细胞质中吸收乳酸离子，