Effect of the F610A Mutation on Substrate Extrusion in the AcrB Transporter: Explanation and Rationale by Molecular Dynamics Simulations

• DOI: 10.1021/ja202666x
• Publication Date: 2011-06-27T17:16:36Z
• Authors: Attilio V. Vargiu; Francesca Collu; Robert Schulz; Klaas M. Pos; Martin Zacharias; Ulrich Kleinekath...; Paolo Ruggerone
• Keywords: Efflux

The tripartite efflux pump AcrAB-TolC is responsible for the intrinsic and acquired multidrug resistance in Escherichia coli. Its active part, homotrimeric transporter AcrB, charge of selective binding substrates energy transduction. mutation F610A has been shown to significantly reduce minimum inhibitory concentration doxorubicin many other substrates, although F610 does not appear interact strongly with them. Biochemical study transport kinetics AcrB yet possible, except some β-lactams, techniques should supply this important information. Therefore, work, we assess impact on functionality by means computational techniques, using as substrate. We found that compound slides deeply inside pocket after mutation, increasing strength interaction. During subsequent conformational alterations transporter, was either extruded from site or displaced along a direction than one associated extrusion. Our indicates how subtle interactions determine transporters, since decreased might be simplistically correlated substrate affinity.