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Publication Abstract from PubMed

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.

Structure 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 LW, Yang H, Rao Z, Li J Nat Commun. 2025 Apr 28;16(1):3969. doi: 10.1038/s41467-025-59300-5. PMID:40295516^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.