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

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.

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Publication Details

Journal
Nature Communications
Published
2025-05-29
DOI
https://doi.org/10.1038/s41467-025-60365-5
Citations
6
Primary Topic
Bacterial Genetics and Biotechnology
Type
article
Field-Weighted Citation Impact
10.90

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article

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

Yuting Ran, Shule Wang, Tianyu Hu, Zhenli Lin et al.
6 citations
Nature Communications
Bacterial Genetics and Biotechnology
10.90
article

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

Yuting Ran, Shule Wang, Tianyu Hu, Zhenli Lin, Xiuna Yang, Gregory Murray Cook, Xiaolin Yang, Zihe Rao, Yao Zhao, Zhi‐Qi Xiong, Luke W. Guddat, William J Jowsey, Matthew B. McNeil, Hazel M Sisson, Bing Zhang, Chenguang Xu, Caitlan J. Smart
article en
6 citations

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.

Nature CommunicationsVol. 16(1)
Translational Research Institute (AU), The University of Queensland (AU), ShanghaiTech University (CN), Shanghai Clinical Research Center (CN), Shenzhen Third People’s Hospital (CN), University of Otago (NZ), Tsinghua University (CN)
National Natural Science Foundation of China, ShanghaiTech University
Good health and well-being
Openalex Percentile: Top 2%
Bacterial Genetics and Biotechnology
10.90
DOIOpen Access PDFOpenAlex
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