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<p>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 <i>Ms</i>Rv1273c/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 <i>Ms</i>Rv1272c. 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 <i>Ms</i>Rv1272c 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年4月28日

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  • 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,
  • Jun Li

摘要

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.