Structure of the MacAB-TolC ABC-type tripartite multidrug efflux pump

Anthony W. P. Fitzpatrick, Salome Llabres, Arthur Neuberger, James N. Blaza, Xiao-Chen Bai, Ui Okada, Satoshi Murakami, Hendrik W. van Veen, Ulrich Zachariae, Sjors H. W. Scheres (Lead / Corresponding author), Ben F. Luisi (Lead / Corresponding author), Dijun Du (Lead / Corresponding author)

Research output: Contribution to journalArticle

39 Citations (Scopus)
111 Downloads (Pure)

Abstract

The MacA-MacB-TolC assembly of Escherichia coli is a transmembrane machine that spans the cell envelope and actively extrudes substrates, including macrolide antibiotics and polypeptide virulence factors. These transport processes are energized by the ATPase MacB, a member of the ATP-binding cassette (ABC) superfamily. We present an electron cryo-microscopy structure of the ABC-type tripartite assembly at near-atomic resolution. A hexamer of the periplasmic protein MacA bridges between a TolC trimer in the outer membrane and a MacB dimer in the inner membrane, generating a quaternary structure with a central channel for substrate translocation. A gating ring found in MacA is proposed to act as a one-way valve in substrate transport. The MacB structure features an atypical transmembrane domain (TMD) with a closely packed dimer interface and a periplasmic opening that is the likely portal for substrate entry from the periplasm, with subsequent displacement through an allosteric transport mechanism.
Original languageEnglish
Article number17070
Pages (from-to)1-8
Number of pages8
JournalNature Microbiology
Volume2
DOIs
Publication statusPublished - 15 May 2017

Fingerprint

Lepidium
Adenosine Triphosphate
Periplasmic Proteins
Cryoelectron Microscopy
Periplasm
Membranes
Macrolides
Virulence Factors
Adenosine Triphosphatases
Escherichia coli
Anti-Bacterial Agents
Peptides

Keywords

  • ABC transporter
  • drug efflux pump
  • multi-drug resistance
  • macrolide transporter
  • toxin transporter

Cite this

Fitzpatrick, A. W. P., Llabres, S., Neuberger, A., Blaza, J. N., Bai, X-C., Okada, U., ... Du, D. (2017). Structure of the MacAB-TolC ABC-type tripartite multidrug efflux pump. Nature Microbiology, 2, 1-8. [17070]. https://doi.org/10.1038/nmicrobiol.2017.70
Fitzpatrick, Anthony W. P. ; Llabres, Salome ; Neuberger, Arthur ; Blaza, James N. ; Bai, Xiao-Chen ; Okada, Ui ; Murakami, Satoshi ; van Veen, Hendrik W. ; Zachariae, Ulrich ; Scheres, Sjors H. W. ; Luisi, Ben F. ; Du, Dijun. / Structure of the MacAB-TolC ABC-type tripartite multidrug efflux pump. In: Nature Microbiology. 2017 ; Vol. 2. pp. 1-8.
@article{992ee51a745c4902b8553df1fba1d045,
title = "Structure of the MacAB-TolC ABC-type tripartite multidrug efflux pump",
abstract = "The MacA-MacB-TolC assembly of Escherichia coli is a transmembrane machine that spans the cell envelope and actively extrudes substrates, including macrolide antibiotics and polypeptide virulence factors. These transport processes are energized by the ATPase MacB, a member of the ATP-binding cassette (ABC) superfamily. We present an electron cryo-microscopy structure of the ABC-type tripartite assembly at near-atomic resolution. A hexamer of the periplasmic protein MacA bridges between a TolC trimer in the outer membrane and a MacB dimer in the inner membrane, generating a quaternary structure with a central channel for substrate translocation. A gating ring found in MacA is proposed to act as a one-way valve in substrate transport. The MacB structure features an atypical transmembrane domain (TMD) with a closely packed dimer interface and a periplasmic opening that is the likely portal for substrate entry from the periplasm, with subsequent displacement through an allosteric transport mechanism.",
keywords = "ABC transporter, drug efflux pump, multi-drug resistance, macrolide transporter, toxin transporter",
author = "Fitzpatrick, {Anthony W. P.} and Salome Llabres and Arthur Neuberger and Blaza, {James N.} and Xiao-Chen Bai and Ui Okada and Satoshi Murakami and {van Veen}, {Hendrik W.} and Ulrich Zachariae and Scheres, {Sjors H. W.} and Luisi, {Ben F.} and Dijun Du",
note = "This work was supported by the Wellcome Trust (B.F.L.), HFSP (B.F.L., H.W.v.V., S. M.), Marie Curie International Outgoing Fellowship (A.W.P.F.), the UK Medical Research Council (MC_UP_A025_1013, to SHWS), Wellcome Trust ISSF award (grant number: WT097818MF), the Scottish Universities’ Physics Alliance (U.Z. and S.L.) and MRC Mitochondrial Biology Unit (Grant number: U105663141). A.N. is the recipient of a Herchel-Smith Scholarship.",
year = "2017",
month = "5",
day = "15",
doi = "10.1038/nmicrobiol.2017.70",
language = "English",
volume = "2",
pages = "1--8",
journal = "Nature Microbiology",
issn = "2058-5276",
publisher = "Nature Publishing Group",

}

Fitzpatrick, AWP, Llabres, S, Neuberger, A, Blaza, JN, Bai, X-C, Okada, U, Murakami, S, van Veen, HW, Zachariae, U, Scheres, SHW, Luisi, BF & Du, D 2017, 'Structure of the MacAB-TolC ABC-type tripartite multidrug efflux pump', Nature Microbiology, vol. 2, 17070, pp. 1-8. https://doi.org/10.1038/nmicrobiol.2017.70

Structure of the MacAB-TolC ABC-type tripartite multidrug efflux pump. / Fitzpatrick, Anthony W. P.; Llabres, Salome; Neuberger, Arthur; Blaza, James N.; Bai, Xiao-Chen; Okada, Ui; Murakami, Satoshi; van Veen, Hendrik W.; Zachariae, Ulrich; Scheres, Sjors H. W. (Lead / Corresponding author); Luisi, Ben F. (Lead / Corresponding author); Du, Dijun (Lead / Corresponding author).

In: Nature Microbiology, Vol. 2, 17070, 15.05.2017, p. 1-8.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Structure of the MacAB-TolC ABC-type tripartite multidrug efflux pump

AU - Fitzpatrick, Anthony W. P.

AU - Llabres, Salome

AU - Neuberger, Arthur

AU - Blaza, James N.

AU - Bai, Xiao-Chen

AU - Okada, Ui

AU - Murakami, Satoshi

AU - van Veen, Hendrik W.

AU - Zachariae, Ulrich

AU - Scheres, Sjors H. W.

AU - Luisi, Ben F.

AU - Du, Dijun

N1 - This work was supported by the Wellcome Trust (B.F.L.), HFSP (B.F.L., H.W.v.V., S. M.), Marie Curie International Outgoing Fellowship (A.W.P.F.), the UK Medical Research Council (MC_UP_A025_1013, to SHWS), Wellcome Trust ISSF award (grant number: WT097818MF), the Scottish Universities’ Physics Alliance (U.Z. and S.L.) and MRC Mitochondrial Biology Unit (Grant number: U105663141). A.N. is the recipient of a Herchel-Smith Scholarship.

PY - 2017/5/15

Y1 - 2017/5/15

N2 - The MacA-MacB-TolC assembly of Escherichia coli is a transmembrane machine that spans the cell envelope and actively extrudes substrates, including macrolide antibiotics and polypeptide virulence factors. These transport processes are energized by the ATPase MacB, a member of the ATP-binding cassette (ABC) superfamily. We present an electron cryo-microscopy structure of the ABC-type tripartite assembly at near-atomic resolution. A hexamer of the periplasmic protein MacA bridges between a TolC trimer in the outer membrane and a MacB dimer in the inner membrane, generating a quaternary structure with a central channel for substrate translocation. A gating ring found in MacA is proposed to act as a one-way valve in substrate transport. The MacB structure features an atypical transmembrane domain (TMD) with a closely packed dimer interface and a periplasmic opening that is the likely portal for substrate entry from the periplasm, with subsequent displacement through an allosteric transport mechanism.

AB - The MacA-MacB-TolC assembly of Escherichia coli is a transmembrane machine that spans the cell envelope and actively extrudes substrates, including macrolide antibiotics and polypeptide virulence factors. These transport processes are energized by the ATPase MacB, a member of the ATP-binding cassette (ABC) superfamily. We present an electron cryo-microscopy structure of the ABC-type tripartite assembly at near-atomic resolution. A hexamer of the periplasmic protein MacA bridges between a TolC trimer in the outer membrane and a MacB dimer in the inner membrane, generating a quaternary structure with a central channel for substrate translocation. A gating ring found in MacA is proposed to act as a one-way valve in substrate transport. The MacB structure features an atypical transmembrane domain (TMD) with a closely packed dimer interface and a periplasmic opening that is the likely portal for substrate entry from the periplasm, with subsequent displacement through an allosteric transport mechanism.

KW - ABC transporter

KW - drug efflux pump

KW - multi-drug resistance

KW - macrolide transporter

KW - toxin transporter

U2 - 10.1038/nmicrobiol.2017.70

DO - 10.1038/nmicrobiol.2017.70

M3 - Article

VL - 2

SP - 1

EP - 8

JO - Nature Microbiology

JF - Nature Microbiology

SN - 2058-5276

M1 - 17070

ER -

Fitzpatrick AWP, Llabres S, Neuberger A, Blaza JN, Bai X-C, Okada U et al. Structure of the MacAB-TolC ABC-type tripartite multidrug efflux pump. Nature Microbiology. 2017 May 15;2:1-8. 17070. https://doi.org/10.1038/nmicrobiol.2017.70