An allosteric transport mechanism for the AcrAB-TolC multidrug efflux pump

Author:

Wang Zhao12,Fan Guizhen3,Hryc Corey F124ORCID,Blaza James N5ORCID,Serysheva Irina I3,Schmid Michael F12,Chiu Wah124,Luisi Ben F6ORCID,Du Dijun6

Affiliation:

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

2. Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, United States

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

4. Graduate Program in Structural and Computational Biology and Molecular Biophysics, Baylor College of Medicine, Houston, United States

5. MRC Mitochondrial Biology Unit, Cambridge Biomedical Campus, Cambridge, United Kingdom

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

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.

Funder

U.S. National Library of Medicine

University of Texas at Austin

Medical Research Council

American Heart Association

National Institutes of Health

Wellcome

Human Frontier Science Program

Publisher

eLife Sciences Publications, Ltd

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

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