Download MendeleyStructure and mechanism of a mycobacterial isoniazid efflux pump MsRv1273c/72c with a degenerate nucleotide-binding site.
Yu, J., Lan, Y., Zhu, C., Chen, Z., Pan, J., Shi, Y., Yang, L., Hu, T., Gao, Y., Zhao, Y., Chen, X., Yang, X., Lu, S., Guddat, L.W., Yang, H., Rao, Z., Li, J.(2025) Nat Commun 16: 3969-3969
- PubMed: 40295516
- DOI: https://doi.org/10.1038/s41467-025-59300-5
- Primary Citation of Related Structures:
8WCW, 8WCX, 8XSR, 8XSS, 8XST, 9IQE, 9IQF, 9IQG, 9KWI - PubMed 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.
Organizational Affiliation:
Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China.
