TY  - JOUR
A1  - Zomot, Elia
A1  - Yardeni, Eliane Hadas
A1  - Vargiu, Attilio Vittorio
A1  - Tam, Heng Keat
A1  - Malloci, Giuliano
A1  - Ramaswamy, Venkata Krishnan
A1  - Perach, Michal
A1  - Ruggerone, Paolo
A1  - Pos, Klaas Martinus
A1  - Bibi, Eitan
T1  - A new critical conformational determinant of multidrug efflux by an MFS transporter
T2  - Journal of molecular biology
N2  - 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.
KW  - MdfA
KW  - major facilitator superfamily
KW  - multidrug resistance
KW  - multidrug transport
KW  - secondary transport
Y1  - 2018
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/50261
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-502611
SN  - 1089-8638
SN  - 0022-2836
N1  - © 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/).
VL  - 430
IS  - 9
SP  - 1368
EP  - 1385
PB  - Elsevier
CY  - Amsterdam [u. a.]
ER  -