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Conformational restriction shapes inhibition of a multidrug efflux adaptor protein

View ORCID ProfileBenjamin Russell Lewis, View ORCID ProfileMuhammad R. Uddin, View ORCID ProfileMohammad Moniruzzaman, Katie M. Kuo, Anna J. Higgins, Laila M. N. Shah, View ORCID ProfileFrank Sobott, View ORCID ProfileJerry M. Parks, View ORCID ProfileDietmar Hammerschmid, James C. Gumbart, View ORCID ProfileHelen I. Zgurskaya, View ORCID ProfileEamonn Reading
doi: https://doi.org/10.1101/2022.12.09.519754
Benjamin Russell Lewis
1Department of Chemistry, Britannia House, 7 Trinity Street, King’s College London, London, SE1 1DB, UK
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  • ORCID record for Benjamin Russell Lewis
Muhammad R. Uddin
2Department of Chemistry and Biochemistry, University of Oklahoma, 101 Stephenson Parkway, Norman, Oklahoma 73019, USA
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  • ORCID record for Muhammad R. Uddin
Mohammad Moniruzzaman
2Department of Chemistry and Biochemistry, University of Oklahoma, 101 Stephenson Parkway, Norman, Oklahoma 73019, USA
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Katie M. Kuo
3School of Chemistry and Biochemistry, Georgia Institute of Technology, 837 State Street NW, Atlanta, Georgia 30332, USA
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Anna J. Higgins
4School of Molecular and Cellular Biology & Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, UK
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Laila M. N. Shah
1Department of Chemistry, Britannia House, 7 Trinity Street, King’s College London, London, SE1 1DB, UK
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Frank Sobott
4School of Molecular and Cellular Biology & Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, UK
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Jerry M. Parks
5Bioscience Division, Oak Ridge National Laboratory, 1 Bethel Valley Rd, Oak Ridge, TN, 37831, USA
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Dietmar Hammerschmid
1Department of Chemistry, Britannia House, 7 Trinity Street, King’s College London, London, SE1 1DB, UK
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James C. Gumbart
3School of Chemistry and Biochemistry, Georgia Institute of Technology, 837 State Street NW, Atlanta, Georgia 30332, USA
6School of Physics, Georgia Institute of Technology, 837 State Street NW, Atlanta, Georgia 30332, USA
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  • For correspondence: eamonn.reading@kcl.ac.uk elenaz@ou.edu gumbart@physics.gatech.edu
Helen I. Zgurskaya
2Department of Chemistry and Biochemistry, University of Oklahoma, 101 Stephenson Parkway, Norman, Oklahoma 73019, USA
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  • For correspondence: eamonn.reading@kcl.ac.uk elenaz@ou.edu gumbart@physics.gatech.edu
Eamonn Reading
1Department of Chemistry, Britannia House, 7 Trinity Street, King’s College London, London, SE1 1DB, UK
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  • For correspondence: eamonn.reading@kcl.ac.uk elenaz@ou.edu gumbart@physics.gatech.edu
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Abstract

Membrane efflux pumps play a major role in bacterial multidrug resistance. The tripartite multidrug efflux pump system from Escherichia coli, AcrAB-TolC, is a target for inhibition to lessen resistance development and restore antibiotic efficacy, with homologs in other ESKAPE pathogens. Here, we rationalize a mechanism of inhibition against the periplasmic adaptor protein, AcrA, using a combination of hydrogen/deuterium exchange mass spectrometry, cellular efflux assays, and molecular dynamics simulations. We define the structural dynamics of AcrA and find that an inhibitor can inflict long-range stabilisation across all four of its domains, whereas an interacting efflux substrate has minimal effect. Our results support a model where an inhibitor forms a molecular wedge within a cleft between the lipoyl and αβ domains of AcrA, diminishing its conformational transmission of drug-evoked signals from AcrB to TolC. This work provides molecular insights into multidrug adaptor protein function which could be valuable for developing antimicrobial therapeutics.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Conformational restriction shapes inhibition of a multidrug efflux adaptor protein
Benjamin Russell Lewis, Muhammad R. Uddin, Mohammad Moniruzzaman, Katie M. Kuo, Anna J. Higgins, Laila M. N. Shah, Frank Sobott, Jerry M. Parks, Dietmar Hammerschmid, James C. Gumbart, Helen I. Zgurskaya, Eamonn Reading
bioRxiv 2022.12.09.519754; doi: https://doi.org/10.1101/2022.12.09.519754
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Conformational restriction shapes inhibition of a multidrug efflux adaptor protein
Benjamin Russell Lewis, Muhammad R. Uddin, Mohammad Moniruzzaman, Katie M. Kuo, Anna J. Higgins, Laila M. N. Shah, Frank Sobott, Jerry M. Parks, Dietmar Hammerschmid, James C. Gumbart, Helen I. Zgurskaya, Eamonn Reading
bioRxiv 2022.12.09.519754; doi: https://doi.org/10.1101/2022.12.09.519754

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