Effect of the F610A mutation on substrate extrusion in the AcrB transporter: Explanation and rationale by molecular dynamics simulations

Attilio V. Vargiu, Francesca Collu, Robert Schulz, Klaas M. Pos, Martin Zacharias, Ulrich Kleinekathöfer, Paolo Ruggerone

Research output: Contribution to journalArticlepeer-review

71 Scopus citations

Abstract

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

Original languageEnglish
Pages (from-to)10704-10707
Number of pages4
JournalJournal of the American Chemical Society
Volume133
Issue number28
DOIs
StatePublished - 20 Jul 2011
Externally publishedYes

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