Maharjan Rakesh, Zhang Zhemin, Klenotic Philip A, Gregor William D, Purdy Georgiana E, Yu Edward W
Department of Pharmacology, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
Department of Molecular Microbiology and Immunology, Oregon Health and Science University, Portland, Oregon, USA.
mBio. 2024 Dec 11;15(12):e0303524. doi: 10.1128/mbio.03035-24. Epub 2024 Oct 31.
, the causative agent of the airborne infection tuberculosis (TB), contains 13 mycobacterial membrane protein large (MmpL) transporters that can be divided into two distinct subclasses. These MmpL proteins play important functional roles within the mycobacterium and subsequently are considered attractive drug targets to combat TB infection. Previously, we reported both X-ray and cryo-electron microscopy (cryo-EM) structures of the MmpL3 transporter, providing high-resolution structural information for this subclass of the MmpL proteins. Thus far, there is no structural information available for the other subclass, which includes MmpL5, an inner membrane transporter that plays a critical role in iron hemostasis. Here, we report the first cryo-EM structure of the MmpL5 transporter bound with the meromycolate extension acyl carrier protein M (AcpM) to a resolution of 2.81 Å. Our structural data reveals that MmpL5 and AcpM interact in the cytoplasm to form a complex, and this allows us to propose that MmpL5 may also associate with the mycobactin L (MbtL) protein in a similar fashion to form a heterocomplex important for iron acquisition, which enables the survival and replication of the mycobacterium.
The emergence and spread of multidrug-resistant tuberculosis (TB) present enormous challenges to the global public health. The causative agent, , has now infected more than one-third of the world's population. Here, we report the first structure of the mycobacterial membrane protein large 5 (MmpL5), an essential transporter for iron acquisition, bound with the meromycolate extension acyl carrier protein M (AcpM), indicating a plausible pathway for mycobactin translocation. Our studies will ultimately inform an era in structure-guided drug design to combat TB infection.
结核分枝杆菌是空气传播感染性疾病结核病（TB）的病原体，它含有13种分枝杆菌膜蛋白大（MmpL）转运蛋白，可分为两个不同的亚类。这些MmpL蛋白在分枝杆菌内发挥重要的功能作用，因此被认为是对抗结核病感染的有吸引力的药物靶点。此前，我们报道了MmpL3转运蛋白的X射线和冷冻电子显微镜（cryo-EM）结构，为该亚类MmpL蛋白提供了高分辨率的结构信息。到目前为止，尚无关于另一个亚类的结构信息，该亚类包括MmpL5，一种在内膜铁稳态中起关键作用的转运蛋白。在这里，我们报道了与分枝菌酸延伸酰基载体蛋白M（AcpM）结合的MmpL5转运蛋白的首个冷冻电镜结构，分辨率为2.81 Å。我们的结构数据表明，MmpL5和AcpM在细胞质中相互作用形成复合物，这使我们推测MmpL5也可能以类似方式与分枝杆菌素L（MbtL）蛋白结合形成对铁摄取很重要的异源复合物，从而使分枝杆菌得以存活和复制。
耐多药结核病（TB）的出现和传播给全球公共卫生带来了巨大挑战。病原体结核分枝杆菌现已感染了世界三分之一以上的人口。在这里，我们报道了分枝杆菌膜蛋白大5（MmpL5）的首个结构，它是铁摄取的必需转运蛋白，与分枝菌酸延伸酰基载体蛋白M（AcpM）结合，表明了分枝杆菌素转运的合理途径。我们的研究最终将为对抗结核病感染的结构导向药物设计时代提供信息。
