A new critical conformational determinant of multidrug efflux by an MFS transporter

  • Secondary multidrug (Mdr) transporters utilize ion concentration gradients to actively remove antibiotics and other toxic compounds from cells. The model Mdr transporter MdfA from Escherichia coli exchanges dissimilar drugs for protons. The transporter should open at the cytoplasmic side to enable access of drugs into the Mdr recognition pocket. Here we show that the cytoplasmic rim around the Mdr recognition pocket represents a previously overlooked important regulatory determinant in MdfA. We demonstrate that increasing the positive charge of the electrically asymmetric rim dramatically inhibits MdfA activity and sometimes even leads to influx of planar, positively charged compounds, resulting in drug sensitivity. Our results suggest that unlike the mutants with the electrically modified rim, the membrane-embedded wild-type MdfA exhibits a significant probability of an inward-closed conformation, which is further increased by drug binding. Since MdfA binds drugs from its inward-facing environment, these results are intriguing and raise the possibility that the transporter has a sensitive, drug-induced conformational switch, which favors an inward-closed state.
Author:Elia Zomot, Eliane Hadas Yardeni, Attilio Vittorio Vargiu, Heng Keat Tam, Giuliano Malloci, Venkata Krishnan Ramaswamy, Michal Perach, Paolo Ruggerone, Klaas Martinus PosORCiD, Eitan Bibi
Pubmed Id:https://pubmed.ncbi.nlm.nih.gov/29530612
Parent Title (English):Journal of molecular biology
Place of publication:Amsterdam [u. a.]
Contributor(s):Nieng Yan
Document Type:Article
Year of Completion:2018
Date of first Publication:2018/03/09
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2019/05/16
Tag:MdfA; major facilitator superfamily; multidrug resistance; multidrug transport; secondary transport
Page Number:18
First Page:1368
Last Page:1385
© 2018 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Institutes:Biochemie, Chemie und Pharmazie / Biochemie und Chemie
Dewey Decimal Classification:5 Naturwissenschaften und Mathematik / 54 Chemie / 540 Chemie und zugeordnete Wissenschaften
Licence (German):License LogoCreative Commons - Namensnennung-Nicht kommerziell - Keine Bearbeitung 4.0