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Review
. 2009 May;1794(5):817-25.
doi: 10.1016/j.bbapap.2009.02.017. Epub 2009 Mar 13.

Assembly and transport mechanism of tripartite drug efflux systems

Rajeev Misra  1 , Vassiliy N Bavro
Affiliations
Review

Assembly and transport mechanism of tripartite drug efflux systems

Rajeev Misra et al. Biochim Biophys Acta. 2009 May.

Abstract

Multidrug efflux (MDR) pumps remove a variety of compounds from the cell into the external environment. There are five different classes of MDR pumps in bacteria, and quite often a single bacterial species expresses multiple classes of pumps. Although under normal circumstances MDR pumps confer low-level intrinsic resistance to drugs, the presence of drugs and mutations in regulatory genes lead to high level expression of MDR pumps that can pose problems with therapeutic treatments. This review focuses on the resistance nodulation cell division (RND)-class of MDR pumps that assemble from three proteins. Significant recent advancement in structural aspects of the three pump components has shed new light on the mechanism by which the tripartite efflux pumps extrude drugs. This new information will be critical in developing inhibitors against MDR pumps to improve the potency of prescribed drugs.

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Figures

Fig. 1
Fig. 1
Structures of TolC (1EK9), AcrA (2F1M) and AcrB (2GIF) and their domains. Note that TolC and AcrB are shown as homotrimers, AcrA as a monomer. Locations of the static H3/H4 and mobile H7/H8 helices from two different TolC protomers are shown. OM and IM refer to the outer membrane and the inner membrane, respectively.
Fig. 2
Fig. 2
Views of the periplasmic aperture of the currently available TolC trimer structures reveal a possible transition to a fully open state. Structures of the closed state (1EK9; left), and partially open mutant structures 2VDE (center) and 2VDD (right) reveal a rearrangement of the periplasmic tip helices consistent with the proposed “aperture opening” mechanism. In the initial state (left) the aperture is maintained closed by inter-protomer salt-bridges, which are thought to become destabilized and released upon the interaction of the OMF with the RND. The following transition is also associated with a breakage of the central three-fold symmetry of the trimer and relaxation of the gating helical pairs (arrows) resulting in a roughly hexagonal arrangement (right).
Fig. 3
Fig. 3
A view of AcrB monomer (2RDD) bound to the YajC helix (green).
See this image and copyright information in PMC

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