In situ structure and assembly of the multidrug efflux pump AcrAB-TolC.
Bell, James M
Nature Publishing Group
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Shi, X., Chen, M., Yu, Z., Bell, J. M., Wang, H., Forrester, I., Villarreal, H., et al. (2019). In situ structure and assembly of the multidrug efflux pump AcrAB-TolC.. Nature communications, 10 (1), 2635. https://doi.org/10.1038/s41467-019-10512-6
Multidrug efflux pumps actively expel a wide range of toxic substrates from the cell and play a major role in intrinsic and acquired drug resistance. In Gram-negative bacteria, these pumps form tripartite assemblies that span the cell envelope. However, the in situ structure and assembly mechanism of multidrug efflux pumps remain unknown. Here we report the in situ structure of the Escherichia coli AcrAB-TolC multidrug efflux pump obtained by electron cryo-tomography and subtomogram averaging. The fully assembled efflux pump is observed in a closed state under conditions of antibiotic challenge and in an open state in the presence of AcrB inhibitor. We also observe intermediate AcrAB complexes without TolC and discover that AcrA contacts the peptidoglycan layer of the periplasm. Our data point to a sequential assembly process in living bacteria, beginning with formation of the AcrAB subcomplex and suggest domains to target with efflux pump inhibitors.
Periplasm, Escherichia coli, Peptidoglycan, Lipoproteins, Bacterial Outer Membrane Proteins, Escherichia coli Proteins, Carrier Proteins, Membrane Transport Proteins, Multidrug Resistance-Associated Proteins, Anti-Bacterial Agents, Cryoelectron Microscopy, Drug Resistance, Multiple, Bacterial, Protein Structure, Quaternary, Protein Binding, Electron Microscope Tomography, Intravital Microscopy
European Commission Horizon 2020 (H2020) ERC (742210)
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External DOI: https://doi.org/10.1038/s41467-019-10512-6
This record's URL: https://www.repository.cam.ac.uk/handle/1810/293605
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