Structures of the mycobacterial MmpL4 and MmpL5 transporters provide insights into their role in siderophore export and iron acquisition

• Published in: PLoS biology Vol. 22; no. 10; p. e3002874
• Main Authors: Maharjan, Rakesh, Zhang, Zhemin, Klenotic, Philip A, Gregor, William D, Tringides, Marios L, Cui, Meng, Purdy, Georgiana E, Yu, Edward W
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 18.10.2024; Public Library of Science (PLoS)
• Subjects: Bacterial Proteins - chemistry; Bacterial Proteins - metabolism; Biological Transport; Biology and Life Sciences; Cryoelectron Microscopy; Iron - metabolism; Membrane Transport Proteins - chemistry; Membrane Transport Proteins - metabolism; Models, Molecular; Mycobacterium smegmatis - metabolism; Mycobacterium tuberculosis - metabolism; Physical Sciences; Proteins; Research and Analysis Methods; Short Reports; Siderophores - metabolism
• ISSN: 1545-7885; 1544-9173; 1545-7885
• DOI: 10.1371/journal.pbio.3002874

The Mycobacterium tuberculosis (Mtb) pathogen, the causative agent of the airborne infection tuberculosis (TB), harbors a number of mycobacterial membrane protein large (MmpL) transporters. These membrane proteins can be separated into 2 distinct subclasses, where they perform important functional roles, and thus, are considered potential drug targets to combat TB. Previously, we reported both X-ray and cryo-EM structures of the MmpL3 transporter, providing high-resolution structural information for this subclass of the MmpL proteins. Currently, there is no structural information available for the subclass associated with MmpL4 and MmpL5, transporters that play a critical role in iron homeostasis of the bacterium. Here, we report cryo-EM structures of the M. smegmatis MmpL4 and MmpL5 transporters to resolutions of 2.95 Å and 3.00 Å, respectively. These structures allow us to propose a plausible pathway for siderophore translocation via these 2 transporters, an essential step for iron acquisition that enables the survival and replication of the mycobacterium.