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; Ben F. Luisi; Dijun Du

doi:10.1038/nmicrobiol.2017.70

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)

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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 language	English
Article number	17070
Pages (from-to)	1-8
Number of pages	8
Journal	Nature Microbiology
Volume	2
DOIs	https://doi.org/10.1038/nmicrobiol.2017.70
Publication status	Published - 15 May 2017

Keywords

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

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10.1038/nmicrobiol.2017.70

Author Accepted ManuscriptAccepted author manuscript, 224 KB

Zachariae, Ulrich
- Biological Chemistry and Drug Discovery - Professor of Molecular Biophysics
Person: Academic

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@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{\textquoteright} 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.",

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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

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SN - 2058-5276

VL - 2

SP - 1

EP - 8

JO - Nature Microbiology

JF - Nature Microbiology

M1 - 17070

ER -

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

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Zachariae, Ulrich

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