Structure and mechanism of a mycobacterial isoniazid efflux pump MsRv1273c/72c with a degenerate nucleotide-binding site

Jing Yu, Yuhui Lan, Chen Zhu, Zhendong Chen, Junyi Pan, Yanfeng Shi, Lan Yang, Tianyu Hu, Yan Gao, Yao Zhao, Xiaobo Chen, Xiuna Yang, Shuihua Lu, Luke W. Guddat, Haitao Yang (), Zihe Rao () and Jun Li ()
Additional contact information
Jing Yu: ShanghaiTech University
Yuhui Lan: ShanghaiTech University
Chen Zhu: ShanghaiTech University
Zhendong Chen: ShanghaiTech University
Junyi Pan: ShanghaiTech University
Yanfeng Shi: ShanghaiTech University
Lan Yang: ShanghaiTech University
Tianyu Hu: ShanghaiTech University
Yan Gao: ShanghaiTech University
Yao Zhao: Shenzhen Third People’s Hospital
Xiaobo Chen: ShanghaiTech University
Xiuna Yang: ShanghaiTech University
Shuihua Lu: Shenzhen Third People’s Hospital
Luke W. Guddat: The University of Queensland
Haitao Yang: ShanghaiTech University
Zihe Rao: ShanghaiTech University
Jun Li: ShanghaiTech University

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract Heterodimeric ATP-binding cassette (ABC) transporters containing one catalytically impaired degenerate nucleotide-binding site (NBS) have a mechanism different from those with two active NBSs. However, the structural basis of their transport mechanism remains to be explained. Here, we determine mycobacterial MsRv1273c/72c to be an isoniazid efflux pump and determine several structures by cryo-electron microscopy showing specific asymmetrical features including an N-terminal extending loop and a periplasmic helical hairpin only found in MsRv1272c. In addition, we capture three distinct asymmetric states where the nucleotide-binding domains are partially dimerized at the degenerate site. Using these intermediate states, the D-WalkerB loop and X-signature loop of MsRv1272c modulate and couple the function of both NBSs through conformational changes. Thus, these data provide insights into the mechanism of this heterodimeric ABC transporter containing a degenerate NBS. The structures also provide a framework for the rational design of anti-tuberculosis drugs targeting this drug-efflux pump.

Date: 2025
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DOI: 10.1038/s41467-025-59300-5

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