Functional Rotation of the Transporter AcrB: The Essentials of Peristaltic Motion and Subsequent Substrate Extrusion

Schulz R;VARGIU, ATTILIO VITTORIO;Collu F;Kleinekathöfer U;RUGGERONE, PAOLO

2010-01-01

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Abstract

Bacteria, such as E. coli, use multidrug efflux pumps to export toxic substrates through their cell membranes, including antibiotics. The RND transporter of the AcrAB-TolC efflux pump is able to export structurally and chemically different substrates via a functional rotation. The three major states of this rotation cycle were found in several asymmetric crystal structures. After initially analyzing the basic mechanisms of opening of the TolC channel [1] and of substrate extrusion by AcrB [2] separately, we have continued the analysis of the latter one. Thereby, we have focused both on the local interactions between substrate and protein, the properties of the extrusion pathway, as well as the principal subdomain movements which lead to the peristaltic motion. Furthermore, we have investigated the possibility to pull the substrate from the final state of the previous simulations out of the exit gate to estimate whether the substrate is already free to leave the protein via diffusion, which is usually beyond the time scale of computer simulations. [1] R. Schulz, U. Kleinekathöfer, Biophys. J. 96, 3116 (2009) [2] R. Schulz, A. Vargiu, F. Collu, U. Kleinekathöfer, P. Ruggerone, submitted