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In situ structure and assembly of the multidrug efflux pump AcrAB-TolC.
Nat Commun 2019; 10(1):2635NC

Abstract

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.

Authors+Show Affiliations

Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX, 77030, USA. Jiangsu Province Key Laboratory of Anesthesiology and Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, China.Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX, 77030, USA.Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX, 77030, USA.Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX, 77030, USA. Graduate Program in Quantitative and Computational Biosciences, Baylor College of Medicine, Houston, TX, 77030, USA.Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX, 77030, USA.CryoEM Core at Baylor College of Medicine, Houston, TX, 77030, USA.CryoEM Core at Baylor College of Medicine, Houston, TX, 77030, USA.CryoEM Core at Baylor College of Medicine, Houston, TX, 77030, USA.Department of Biochemistry, University of Cambridge, Cambridge, CB21GA, UK. School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China.Department of Biochemistry, University of Cambridge, Cambridge, CB21GA, UK.Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX, 77030, USA.Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX, 77030, USA. zhaow@bcm.edu. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, 77030, USA. zhaow@bcm.edu.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

31201302

Citation

Shi, Xiaodong, et al. "In Situ Structure and Assembly of the Multidrug Efflux Pump AcrAB-TolC." Nature Communications, vol. 10, no. 1, 2019, p. 2635.
Shi X, Chen M, Yu Z, et al. In situ structure and assembly of the multidrug efflux pump AcrAB-TolC. Nat Commun. 2019;10(1):2635.
Shi, X., Chen, M., Yu, Z., Bell, J. M., Wang, H., Forrester, I., ... Wang, Z. (2019). In situ structure and assembly of the multidrug efflux pump AcrAB-TolC. Nature Communications, 10(1), p. 2635. doi:10.1038/s41467-019-10512-6.
Shi X, et al. In Situ Structure and Assembly of the Multidrug Efflux Pump AcrAB-TolC. Nat Commun. 2019 06 14;10(1):2635. PubMed PMID: 31201302.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - In situ structure and assembly of the multidrug efflux pump AcrAB-TolC. AU - Shi,Xiaodong, AU - Chen,Muyuan, AU - Yu,Zhili, AU - Bell,James M, AU - Wang,Hans, AU - Forrester,Isaac, AU - Villarreal,Heather, AU - Jakana,Joanita, AU - Du,Dijun, AU - Luisi,Ben F, AU - Ludtke,Steven J, AU - Wang,Zhao, Y1 - 2019/06/14/ PY - 2019/03/01/received PY - 2019/05/08/accepted PY - 2019/6/16/entrez PY - 2019/6/16/pubmed PY - 2019/7/10/medline SP - 2635 EP - 2635 JF - Nature communications JO - Nat Commun VL - 10 IS - 1 N2 - 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. SN - 2041-1723 UR - https://www.unboundmedicine.com/medline/citation/31201302/In_situ_structure_and_assembly_of_the_multidrug_efflux_pump_AcrAB_TolC_ L2 - http://dx.doi.org/10.1038/s41467-019-10512-6 DB - PRIME DP - Unbound Medicine ER -