Molecular basis for multidrug efflux by an anaerobic-associated RND transporter

Ryan Lawrence, Mohd Athar, Muhammad R. Uddin, Christopher Adams, Joana S. Sousa, Oliver Durrant, Sophie Lellman, Lucy Sutton, C. William Keevil, Nisha Patel, Christine E. Prosser, David McMillan, Helen I. Zgurskaya, Attilio V. Vargiu, Zainab Ahdash () and Eamonn Reading ()
Additional contact information
Ryan Lawrence: University of Southampton, School of Biological Sciences
Mohd Athar: S.P. Monserrato-Sestu, Department of Physics, University of Cagliari, Cittadella Universitaria
Muhammad R. Uddin: University of Oklahoma, Department of Chemistry and Biochemistry
Christopher Adams: UCB Biopharma, Department of Protein Structure and Biophysics
Joana S. Sousa: UCB Biopharma, Department of Protein Structure and Biophysics
Oliver Durrant: UCB Biopharma, Department of Protein Structure and Biophysics
Sophie Lellman: UCB Biopharma, Department of Protein Structure and Biophysics
Lucy Sutton: University of Southampton, School of Biological Sciences
C. William Keevil: University of Southampton, School of Biological Sciences
Nisha Patel: UCB Biopharma, Department of Protein Structure and Biophysics
Christine E. Prosser: UCB Biopharma, Department of Protein Structure and Biophysics
David McMillan: UCB Biopharma, Department of Protein Structure and Biophysics
Helen I. Zgurskaya: University of Oklahoma, Department of Chemistry and Biochemistry
Attilio V. Vargiu: S.P. Monserrato-Sestu, Department of Physics, University of Cagliari, Cittadella Universitaria
Zainab Ahdash: UCB Biopharma, Department of Protein Structure and Biophysics
Eamonn Reading: University of Southampton, School of Biological Sciences

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract Bacteria can resist antibiotics and toxic substances within demanding ecological settings, such as low oxygen, extreme acid, and during nutrient starvation. MdtEF, a proton motive force-driven efflux pump from the resistance-nodulation-cell division (RND) superfamily, is upregulated in these conditions but its molecular mechanism is unknown. Here, we report cryo-electron microscopy structures of Escherichia coli multidrug transporter MdtF within native-lipid nanodiscs, including a single-point mutant with an altered multidrug phenotype and associated substrate-bound form. Drug binding domain and channel conformational plasticity likely governs substrate polyspecificity, analogous to closely related, constitutively expressed counterpart, AcrB. Whereas we discover distinct transmembrane state transitions within MdtF, which create a more engaged proton relay network, altered drug transport allostery and an acid-responsive increase in efflux efficiency. Our findings provide mechanistic insights necessary to understand bacterial xenobiotic and toxin removal by MdtF and its role within nutrient-depleted and acid stress settings, as endured in the gastrointestinal tract.

Date: 2025
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-025-65565-7 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-65565-7

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-025-65565-7

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().