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A Structural Model of EmrE, a Multi-Drug Transporter from Escherichia coli

Kay-Eberhard Gottschalk ^*, Misha Soskine , Shimon Schuldiner  and Horst Kessler ^*

^* Institut für Chemie und Biochemie II, Technische Universität München, Garching, Germany; and Alexander Silberman Institute of Life Sciences, Hebrew University of Jerusalem, Jerusalem 91904, Israel

Correspondence: Address reprint requests to Horst Kessler, Tel.: 49-89-28913301; Fax: 49-89-28913210; E-mail: horst.kessler{at}ch.tum.de.

Using a recently reported computational method, we describe an approach to model the structure of EmrE, a proton coupled multi-drug transporter of Escherichia coli. EmrE is the smallest ion-coupled transporter known; it functions as an oligomer and each monomer comprises four transmembrane segments. Because of its size, EmrE provides a unique experimental paradigm. The computational method does not afford a unique solution for the monomer. The experimental constraints available were used to select the most likely structure and to dock two monomers together to yield a dimer. The model is further validated by modeling of Hsmr, an EmrE homolog with a remarkable amino acid composition with over 40% of Ala and Val. The Hsmr model is similar to that of EmrE, with the majority of the Ala or Val residues facing the lipid. In addition, the model of EmrE features a putative substrate-binding site very similar to that observed in BmrR, a transcription activator of multi-drug transporters, with a similar substrate profile. The two crucial residues that couple proton fluxes with substrate binding in the homo-dimer of EmrE, Glu-14, have a spatial arrangement that agrees with proposed molecular mechanisms of transport.

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