A New Critical Conformational Determinant of Multidrug Efflux by an MFS Transporter.
J Mol Biol
; 430(9): 1368-1385, 2018 04 27.
Article
en En
| MEDLINE
| ID: mdl-29530612
ABSTRACT
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.
Palabras clave
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Proteínas de Transporte de Membrana
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Proteínas de Escherichia coli
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Escherichia coli
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Mutación
Idioma:
En
Revista:
J Mol Biol
Año:
2018
Tipo del documento:
Article
País de afiliación:
Israel