An allosteric transport mechanism for the AcrAB-TolC Multidrug Efflux Pump

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Abstract

Bacterial efflux pumps confer multidrug resistance by transporting diverse antibiotics from the cell. In Gram-negative bacteria, some of these pumps form multi-protein assemblies that span the cell envelope. Here we report the near-atomic resolution cryoEM structures of the Escherichia coli AcrAB-TolC multidrug efflux pump in resting and drug transport states, revealing a quaternary structural switch that allosterically couples and synchronizes initial ligand binding with channel opening. Within the transport-activated state, the channel remains open even though the pump cycles through three distinct conformations. Collectively, our data provide a dynamic mechanism for the assembly and operation of the AcrAB-TolC pump.

Data availability

The following data sets were generated

1. D. Du
2. B.F. Luisi
(2017) Crystal structure of AcrBZ complex: 2017
Publicly available at PDB (accession no: 5NC5).

http://www.wwpdb.org
1. Z. Wang
2. G. Fen
3. C.F. Hryc
4. J.N. Blaze
5. I.I. Serysheva
6. M.F. Schmid
7. W. Chiu
8. B.F. Luisi
9. D. Du
(2017) The apo structure of AcrAB-TolC tripartite multidrug efflux pump: 2017
Publicly available at EBI Protein Data Bank (accession no: EMD-8636).

https://www.ebi.ac.uk/pdbe/emdb/
1. Z. Wang
2. G. Fen
3. C.F. Hryc
4. J.N. Blaze
5. I.I. Serysheva
6. M.F. Schmid
7. W. Chiu
8. B.F. Luisi
9. D. Du.
(2017) The asymmetric structure of AcrAB-TolC tripartite multidrug efflux pump: 2017
Publicly available at EBI Protein Data Bank (accession no: EMD-8640).

https://www.ebi.ac.uk/pdbe/emdb/
1. Z. Wang
2. G. Fen
3. C.F. Hryc
4. J.N. Blaze
5. I.I. Serysheva
6. M.F. Schmid
7. W. Chiu
8. B.F. Luisi
9. D. Du. 2017
(2017) The symmetric structure of AcrAB-TolC tripartite multidrug efflux pump with inhibitor MBX3132 bound: 2017
Publicly available at EBI Protein Data Bank (accession no: EMD-3636).

https://www.ebi.ac.uk/pdbe/emdb/
1. Z. Wang
2. G. Fen
3. C.F. Hryc
4. J.N. Blaze
5. I.I. Serysheva
6. M.F. Schmid
7. W. Chiu
8. B.F. Luisi
9. D. Du.
(2017) The apo structure of AcrAB-TolC tripartite multidrug efflux pump: 2017
Publicly available at PDB (accession no: 5V5S).

http://www.wwpdb.org
1. Z. Wang
2. G. Fen
3. C.F. Hryc
4. J.N. Blaze
5. I.I. Serysheva
6. M.F. Schmid
7. W. Chiu
8. B.F. Luisi
9. D. Du.
(2017) The asymmetric structure of AcrAB-TolC tripartite multidrug efflux pump: 2017
Publicly available at PDB (accession no: 5V78).

http://www.wwpdb.org
1. Z. Wang
2. G. Fen
3. C.F. Hryc
4. J.N. Blaze
5. I.I. Serysheva
6. M.F. Schmid
7. W. Chiu
8. B.F. Luisi
9. D. Du.
(2017) The symmetric structure of AcrAB-TolC tripartite multidrug efflux pump with inhibitor MBX3132 bound: 2017
Publicly available at PDB (accession no: 5NG5).

http://www.wwpdb.org

Article and author information

Author details

Zhao Wang

National Center for Macromolecular Imaging, Baylor College of Medicine, Houston, United States

Competing interests
The authors declare that no competing interests exist.
Guizhen Fan

Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston Medical School, Houston, United States

Competing interests
The authors declare that no competing interests exist.
Corey F Hryc

National Center for Macromolecular Imaging, Baylor College of Medicine, Houston, United States

Competing interests
The authors declare that no competing interests exist.
James N Blaza

MRC Mitochondrial Biology Unit, Cambridge, United Kingdom

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-5420-2116
Irina I Serysheva

Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston Medical School, Houston, United States

Competing interests
The authors declare that no competing interests exist.
Michael F Schmid

National Center for Macromolecular Imaging, Baylor College of Medicine, Houston, United States

Competing interests
The authors declare that no competing interests exist.
Wah Chiu

National Center for Macromolecular Imaging, Baylor College of Medicine, Houston, United States

For correspondence
wah@bcm.edu

Competing interests
The authors declare that no competing interests exist.
Ben F Luisi

Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom

For correspondence
bfl20@cam.ac.uk

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0003-1144-9877
Dijun Du

Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom

For correspondence
dd339@cam.ac.uk

Competing interests
The authors declare that no competing interests exist.

Funding

Wellcome

Ben F Luisi

Human Frontier Science Program

Ben F Luisi

National Institutes of Health (P41GM103832)

Wah Chiu

American Heart Association (16GRNT29720001)

Irina I Serysheva

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.