Ligand binding by the small multidrug-resistant transporter EmrE.

Abstract

EmrE is a member of the Small Multidrug-Resistant (SMR) Transporter family found in E. coli. It utilizes the proton motive force across the inner membrane to drive the efflux of drug molecules, with a proton:drug stoichiometry of 2:1. A well-known binding pocket comprises two glutamates Glu14 near the center of the protein. Similar to many secondary transporters, this “main pocket” binds to both ligands that it antiports. Growing experimental evidence has suggested a peripheral ligand binding site. Drug binding to this peripheral site should not incur large conformation changes but may affect the proton transport. Other evidence has inferred a key role for a less studied His110 residue that is distant from Glu14s. In this work, we have simulated the binding of a model drug TPP+ to EmrE, and identified a peripheral binding site defined by His110. The binding affinity was estimated to be ∼3 kcal/mol. This interaction mode between His110 and the ligand was determined to be largely a cation-pi interaction.