Structure and assembly of the MmpL5/MmpS5 efflux transporter from Mycobacterium tuberculosis

Zhiqi Xiong, Xiaolin Yang, Shule Wang, Caitlan J. Smart, Hazel M. Sisson, Zhenli Lin, Tianyu Hu, Yuting Ran, Chuyao Xu, Xiuna Yang, Yao Zhao, William J. Jowsey, Gregory M. Cook, Matthew B. McNeil, Luke W. Guddat, Zihe Rao () and Bing Zhang ()
Additional contact information
Zhiqi Xiong: ShanghaiTech University
Xiaolin Yang: Shenzhen Third People’s Hospital
Shule Wang: ShanghaiTech University
Caitlan J. Smart: University of Otago
Hazel M. Sisson: University of Otago
Zhenli Lin: ShanghaiTech University
Tianyu Hu: ShanghaiTech University
Yuting Ran: ShanghaiTech University
Chuyao Xu: ShanghaiTech University
Xiuna Yang: ShanghaiTech University
Yao Zhao: Shenzhen Third People’s Hospital
William J. Jowsey: University of Otago
Gregory M. Cook: University of Otago
Matthew B. McNeil: University of Otago
Luke W. Guddat: The University of Queensland
Zihe Rao: ShanghaiTech University
Bing Zhang: ShanghaiTech University

Nature Communications, 2025, vol. 16, issue 1, 1-11

Abstract: Abstract The MmpL5/MmpS5 efflux system in Mycobacterium tuberculosis plays crucial roles in extruding therapeutic drugs (e.g., bedaquiline), and exporting siderophores (i.e., (carboxy)mycobactins). However, the molecular basis underlying these processes remains unknown due to the lack of structural information. Here, we report the cryo-electron microscopy structures of Mycobacterium tuberculosis MmpL5/MmpS5 at resolutions ranging from 2.64 to 3.31 Å, revealing it to be a trimer. The core of this complex is formed by three MmpL5 subunits assembled in a unique shoulder-to-shoulder ring-like configuration, with each MmpS5 subunit positioned between the two adjacent MmpL5 subunits. A remarkable feature of this system is the extracellular stalk, which spans approximately 130 Å in length and is composed of three intertwined anti-parallel coiled-coil portions of MmpL5. The stalk secures the tight association of the three MmpL5 subunits and exhibits intrinsic structural flexibility. Additionally, an unexpected MmpL5 binder, AcpM, a mycobacterial acyl carrier protein, has also been identified. Collectively, the study provides insights into the biological assembly and molecular function of MmpL5/MmpS5, which will facilitate the discovery of innovative inhibitors for this system.

Date: 2025
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DOI: 10.1038/s41467-025-60365-5

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