The mycobacterial membrane protein large 3 (MmpL3) transporter is essential and required for shuttling the lipid trehalose monomycolate (TMM), a precursor of mycolic acid (MA)-containing trehalose dimycolate (TDM) and mycolyl arabinogalactan peptidoglycan (mAGP), in Mycobacterium species, including Mycobacterium tuberculosis and Mycobacterium smegmatis. However, the mechanism that MmpL3 uses to facilitate the transport of fatty acids and lipidic elements to the mycobacterial cell wall remains elusive. Here, we report 7 structures of the M. smegmatis MmpL3 transporter in its unbound state and in complex with trehalose 6-decanoate (T6D) or TMM using single-particle cryo-electron microscopy (cryo-EM) and X-ray crystallography. Combined with calculated results from molecular dynamics (MD) and target MD simulations, we reveal a lipid transport mechanism that involves a coupled movement of the periplasmic domain and transmembrane helices of the MmpL3 transporter that facilitates the shuttling of lipids to the mycobacterial cell wall.

中文翻译：

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分枝杆菌膜蛋白 MmpL3 的结构揭示了其脂质转运机制。

分枝杆菌膜蛋白大 3 (MmpL3) 转运蛋白是必需的，并且是穿梭脂质海藻糖单分枝杆菌酸酯 (TMM) 所必需的，它是分枝杆菌属物种中含有分枝菌酸 (MA) 的海藻糖二分枝菌酸酯 (TDM) 和分枝杆菌基阿拉伯半乳聚糖肽聚糖 (mAGP) 的前体，包括结核分枝杆菌和耻垢分枝杆菌。然而，MmpL3 用于促进脂肪酸和脂质元素向分枝杆菌细胞壁转运的机制仍然难以捉摸。在这里，我们使用单粒子低温电子显微镜 (cryo-EM) 和 X 射线晶体学报告了 7 种非结合状态的耻垢分枝杆菌 MmpL3 转运蛋白结构以及与海藻糖 6-癸酸酯 (T6D) 或 TMM 的复合物。结合分子动力学 (MD) 和目标 MD 模拟的计算结果，