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This content will become publicly available on October 5, 2018

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

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:
 [1] ; ORCiD logo [2] ;  [3] ;  [4] ; ORCiD logo [2] ;  [1]
  1. Goethe Univ. Frankfurt, Frankfurt am Main (Germany)
  2. Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
  3. Goethe Univ. Frankfurt, Frankfurt am Main (Germany); Engelhard Arzneimittel GmbH & Co. KG, Niederdorfelden (Germany)
  4. Middle Tennessee State Univ., Murfreesboro, TN (United States)
Publication Date:
Report Number(s):
LA-UR-17-28721
Journal ID: ISSN 0022-2836; TRN: US1703120
Grant/Contract Number:
AC52-06NA25396
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
Research Org:
Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
Sponsoring Org:
USDOE Laboratory Directed Research and Development (LDRD) Program
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; Biological Science
OSTI Identifier:
1402663