Switch loop flexibility affects substrate transport of the AcrB efflux pump

Muller, Reinke T.; Travers, Timothy; Cha, Hi-jea; Phillips, Joshua L.; Gnanakaran, Sandrasegaram; Pos, Klaas M.

doi:10.1016/j.jmb.2017.09.018

Title: Switch loop flexibility affects substrate transport of the AcrB efflux pump

Abstract

The functionally important switch-loop of the trimeric multidrug transporter AcrB separates the access and deep drug binding pockets in every protomer. This loop, comprising 11 amino acid residues, has been shown to be crucial for substrate transport, as drugs have to travel past the loop to reach the deep binding pocket and from there are transported outside the cell via the connected AcrA and TolC channels. It contains four symmetrically arranged glycine residues suggesting that flexibility is a key feature for pump activity. Upon combinatorial substitution of these glycine residues to proline, functional and structural asymmetry was observed. Proline substitutions on the PC1 proximal side completely abolished transport and reduced backbone flexibility of the switch loop, which adopted a conformation restricting the pathway towards the deep binding pocket. Here, two phenylalanine residues located adjacent to the substitution sensitive glycine residues play a role in blocking the pathway upon rigidification of the loop, since the removal of the phenyl rings from the rigid loop restores drug transport activity.

Authors:

Muller, Reinke T. ^[1];

^[2]; Cha, Hi-jea ^[3]; Phillips, Joshua L. ^[4];

^[2]; Pos, Klaas M. ^[1]

Goethe Univ. Frankfurt, Frankfurt am Main (Germany)
Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
Goethe Univ. Frankfurt, Frankfurt am Main (Germany); Engelhard Arzneimittel GmbH & Co. KG, Niederdorfelden (Germany)
Middle Tennessee State Univ., Murfreesboro, TN (United States)

Publication Date:: 2017-10-05

Research Org.:: Los Alamos National Lab. (LANL), Los Alamos, NM (United States)

Sponsoring Org.:: USDOE Laboratory Directed Research and Development (LDRD) Program

OSTI Identifier:: 1402663

Alternate Identifier(s):: OSTI ID: 1549482

Report Number(s):: LA-UR-17-28721
Journal ID: ISSN 0022-2836; TRN: US1703120

Grant/Contract Number:: AC52-06NA25396

Resource Type:: Accepted Manuscript

Journal Name:: Journal of Molecular Biology

Additional Journal Information:: Journal Volume: 429; Journal Issue: 24; Journal ID: ISSN 0022-2836

Publisher:: Elsevier

Country of Publication:: United States

Language:: English

Subject:: 59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; Biological Science

Citation Formats


                    Muller, Reinke T., Travers, Timothy, Cha, Hi-jea, Phillips, Joshua L., Gnanakaran, Sandrasegaram, and Pos, Klaas M.. Switch loop flexibility affects substrate transport of the AcrB efflux pump.  United States: N. p., 2017. 
Web.  doi:10.1016/j.jmb.2017.09.018.

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                    Muller, Reinke T., Travers, Timothy, Cha, Hi-jea, Phillips, Joshua L., Gnanakaran, Sandrasegaram, & Pos, Klaas M.. Switch loop flexibility affects substrate transport of the AcrB efflux pump.  United States.  https://doi.org/10.1016/j.jmb.2017.09.018

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                    Muller, Reinke T., Travers, Timothy, Cha, Hi-jea, Phillips, Joshua L., Gnanakaran, Sandrasegaram, and Pos, Klaas M.. Thu .  
"Switch loop flexibility affects substrate transport of the AcrB efflux pump".  United States.  https://doi.org/10.1016/j.jmb.2017.09.018.  https://www.osti.gov/servlets/purl/1402663.

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@article{osti_1402663,

  title        = {Switch loop flexibility affects substrate transport of the AcrB efflux pump},

  author       = {Muller, Reinke T. and Travers, Timothy and Cha, Hi-jea and Phillips, Joshua L. and Gnanakaran, Sandrasegaram and Pos, Klaas M.},

  abstractNote = {The functionally important switch-loop of the trimeric multidrug transporter AcrB separates the access and deep drug binding pockets in every protomer. This loop, comprising 11 amino acid residues, has been shown to be crucial for substrate transport, as drugs have to travel past the loop to reach the deep binding pocket and from there are transported outside the cell via the connected AcrA and TolC channels. It contains four symmetrically arranged glycine residues suggesting that flexibility is a key feature for pump activity. Upon combinatorial substitution of these glycine residues to proline, functional and structural asymmetry was observed. Proline substitutions on the PC1 proximal side completely abolished transport and reduced backbone flexibility of the switch loop, which adopted a conformation restricting the pathway towards the deep binding pocket. Here, two phenylalanine residues located adjacent to the substitution sensitive glycine residues play a role in blocking the pathway upon rigidification of the loop, since the removal of the phenyl rings from the rigid loop restores drug transport activity.},

  doi          = {10.1016/j.jmb.2017.09.018},

  journal      = {Journal of Molecular Biology},

  number       = 24,

  volume       = 429,

  place        = {United States},

  year         = {2017},

  month        = {10}

}

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Works referencing / citing this record:

AcrB: a mean, keen, drug efflux machine
journal, September 2019

Kobylka, Jessica; Kuth, Miriam S.; Müller, Reinke T.
Annals of the New York Academy of Sciences, Vol. 1459, Issue 1
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Efflux pump inhibitors of clinically relevant multidrug resistant bacteria
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Lamut, Andraž; Peterlin Mašič, Lucija; Kikelj, Danijel
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Title: Switch loop flexibility affects substrate transport of the AcrB efflux pump

Abstract

Citation Formats

Structural basis of RND-type multidrug exporters journal, April 2015

Assembly and operation of bacterial tripartite multidrug efflux pumps journal, May 2015

RND Efflux Pumps: Structural Information Translated into Function and Inhibition Mechanisms journal, December 2013

Mechanisms of RND multidrug efflux pumps journal, May 2009

Crystal structure of the bacterial membrane protein TolC central to multidrug efflux and protein export journal, June 2000

Conformational Flexibility in the Multidrug Efflux System Protein AcrA journal, March 2006

Crystal structure of bacterial multidrug efflux transporter AcrB journal, October 2002

Crystal structures of a multidrug transporter reveal a functionally rotating mechanism journal, August 2006

Structural Asymmetry of AcrB Trimer Suggests a Peristaltic Pump Mechanism journal, September 2006

Drug Export Pathway of Multidrug Exporter AcrB Revealed by DARPin Inhibitors journal, December 2006

Structure of the AcrAB–TolC multidrug efflux pump journal, April 2014

Structure of the Tripartite Multidrug Efflux Pump AcrAB-TolC Suggests an Alternative Assembly Mode journal, January 2015

Molecular architecture of the bacterial tripartite multidrug efflux pump focusing on the adaptor bridging model journal, May 2015

Tripartite assembly of RND multidrug efflux pumps journal, February 2016

Drug transport mechanism of the AcrB efflux pump journal, May 2009

The atp Synthase—A Splendid Molecular Machine journal, June 1997

Switch-Loop Flexibility Affects Transport of Large Drugs by the Promiscuous AcrB Multidrug Efflux Transporter journal, June 2014

Threonine-978 in the Transmembrane Segment of the Multidrug Efflux Pump AcrB of Escherichia coli Is Crucial for Drug Transport as a Probable Component of the Proton Relay Network journal, October 2006

Crucial Role of Asp408 in the Proton Translocation Pathway of Multidrug Transporter AcrB: Evidence from Site-Directed Mutagenesis and Carbodiimide Labeling journal, May 2009

Conformation of the AcrB Multidrug Efflux Pump in Mutants of the Putative Proton Relay Pathway journal, October 2006

AcrB Trimer Stability and Efflux Activity, Insight from Mutagenesis Studies journal, December 2011

Analysis of AcrB and AcrB/DARPin ligand complexes by LILBID MS journal, September 2011

Structures of the multidrug exporter AcrB reveal a proximal multisite drug-binding pocket journal, November 2011

Transport of drugs by the multidrug transporter AcrB involves an access and a deep binding pocket that are separated by a switch-loop journal, March 2012

Site-Directed Mutagenesis Reveals Putative Substrate Binding Residues in the Escherichia coli RND Efflux Pump AcrB journal, October 2008

Site-Directed Mutagenesis Reveals Amino Acid Residues in the Escherichia coli RND Efflux Pump AcrB That Confer Macrolide Resistance journal, January 2009

Structures of Gate Loop Variants of the AcrB Drug Efflux Pump Bound by Erythromycin Substrate journal, July 2016

Unidirectional peristaltic movement in multisite drug binding pockets of AcrB from molecular dynamics simulations journal, January 2012

Structure validation by Cα geometry: ϕ,ψ and Cβ deviation journal, January 2003

Residue – Residue Potentials with a Favorable Contact Pair Term and an Unfavorable High Packing Density Term, for Simulation and Threading journal, March 1996

A Smoothed Backbone-Dependent Rotamer Library for Proteins Derived from Adaptive Kernel Density Estimates and Regressions journal, June 2011

Structural basis for the inhibition of bacterial multidrug exporters journal, June 2013

Coupling of remote alternating-access transport mechanisms for protons and substrates in the multidrug efflux pump AcrB journal, September 2014

Molecular basis for inhibition of AcrB multidrug efflux pump by novel and powerful pyranopyridine derivatives journal, March 2016

NIH Image to ImageJ: 25 years of image analysis journal, June 2012

NMR-Based Protein Potentials journal, August 2010

A smooth particle mesh Ewald method journal, November 1995

P-LINCS: A Parallel Linear Constraint Solver for Molecular Simulation journal, December 2007

Settle: An analytical version of the SHAKE and RATTLE algorithm for rigid water models journal, October 1992

Canonical sampling through velocity rescaling journal, January 2007

Polymorphic transitions in single crystals: A new molecular dynamics method journal, December 1981

GROMACS: Fast, flexible, and free journal, January 2005

GROMACS 3.0: a package for molecular simulation and trajectory analysis journal, August 2001

GROMACS: A message-passing parallel molecular dynamics implementation journal, September 1995

AcrB: a mean, keen, drug efflux machine journal, September 2019

Efflux pump inhibitors of clinically relevant multidrug resistant bacteria journal, April 2019

Structural basis of RND-type multidrug exporters
journal, April 2015

Assembly and operation of bacterial tripartite multidrug efflux pumps
journal, May 2015

RND Efflux Pumps: Structural Information Translated into Function and Inhibition Mechanisms
journal, December 2013

Mechanisms of RND multidrug efflux pumps
journal, May 2009

Crystal structure of the bacterial membrane protein TolC central to multidrug efflux and protein export
journal, June 2000

Conformational Flexibility in the Multidrug Efflux System Protein AcrA
journal, March 2006

Crystal structure of bacterial multidrug efflux transporter AcrB
journal, October 2002

Crystal structures of a multidrug transporter reveal a functionally rotating mechanism
journal, August 2006

Structural Asymmetry of AcrB Trimer Suggests a Peristaltic Pump Mechanism
journal, September 2006

Drug Export Pathway of Multidrug Exporter AcrB Revealed by DARPin Inhibitors
journal, December 2006

Structure of the AcrAB–TolC multidrug efflux pump
journal, April 2014

Structure of the Tripartite Multidrug Efflux Pump AcrAB-TolC Suggests an Alternative Assembly Mode
journal, January 2015

Molecular architecture of the bacterial tripartite multidrug efflux pump focusing on the adaptor bridging model
journal, May 2015

Tripartite assembly of RND multidrug efflux pumps
journal, February 2016

Drug transport mechanism of the AcrB efflux pump
journal, May 2009

The atp Synthase—A Splendid Molecular Machine
journal, June 1997

Switch-Loop Flexibility Affects Transport of Large Drugs by the Promiscuous AcrB Multidrug Efflux Transporter
journal, June 2014

Threonine-978 in the Transmembrane Segment of the Multidrug Efflux Pump AcrB of Escherichia coli Is Crucial for Drug Transport as a Probable Component of the Proton Relay Network
journal, October 2006

Crucial Role of Asp408 in the Proton Translocation Pathway of Multidrug Transporter AcrB: Evidence from Site-Directed Mutagenesis and Carbodiimide Labeling
journal, May 2009

Conformation of the AcrB Multidrug Efflux Pump in Mutants of the Putative Proton Relay Pathway
journal, October 2006

AcrB Trimer Stability and Efflux Activity, Insight from Mutagenesis Studies
journal, December 2011

Analysis of AcrB and AcrB/DARPin ligand complexes by LILBID MS
journal, September 2011

Structures of the multidrug exporter AcrB reveal a proximal multisite drug-binding pocket
journal, November 2011

Transport of drugs by the multidrug transporter AcrB involves an access and a deep binding pocket that are separated by a switch-loop
journal, March 2012

Site-Directed Mutagenesis Reveals Putative Substrate Binding Residues in the Escherichia coli RND Efflux Pump AcrB
journal, October 2008

Site-Directed Mutagenesis Reveals Amino Acid Residues in the Escherichia coli RND Efflux Pump AcrB That Confer Macrolide Resistance
journal, January 2009

Structures of Gate Loop Variants of the AcrB Drug Efflux Pump Bound by Erythromycin Substrate
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