Mycobacterium tuberculosis, 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 Mycobacterium smegmatis 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.
Importance: The emergence and spread of multidrug-resistant tuberculosis (TB) present enormous challenges to the global public health. The causative agent, Mycobacterium tuberculosis, 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.
Keywords: MmpL5; Mycobacterial membrane protein Large; acyl carrier protein M; iron acquisition; mycobactin L; siderophore export.