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Structural basis of RND-type multidrug exporters.

Yamaguchi A, Nakashima R, Sakurai K - Front Microbiol (2015)

Bottom Line: Multidrug recognition is based on a multisite drug-binding mechanism, in which two voluminous multidrug-binding pockets in cell membrane exporters recognize a wide range of substrates as a result of permutations at numerous binding sites that are specific for the partial structures of substrate molecules.Substrates are transported through dual multidrug-binding pockets via the peristaltic motion of the substrate translocation channel.Although there are no clinically available inhibitors of bacterial multidrug exporters, efforts to develop inhibitors based on structural information are underway.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Cell Membrane Structural Biology, Institute of Scientific and Industrial Research, Osaka University Ibaraki, Japan.

ABSTRACT
Bacterial multidrug exporters are intrinsic membrane transporters that act as cellular self-defense mechanism. The most notable characteristics of multidrug exporters is that they export a wide range of drugs and toxic compounds. The overexpression of these exporters causes multidrug resistance. Multidrug-resistant pathogens have become a serious problem in modern chemotherapy. Over the past decade, investigations into the structure of bacterial multidrug exporters have revealed the multidrug recognition and export mechanisms. In this review, we primarily discuss RND-type multidrug exporters particularly AcrAB-TolC, major drug exporter in Gram-negative bacteria. RND-type drug exporters are tripartite complexes comprising a cell membrane transporter, an outer membrane channel and an adaptor protein. Cell membrane transporters and outer membrane channels are homo-trimers; however, there is no consensus on the number of adaptor proteins in these tripartite complexes. The three monomers of a cell membrane transporter have varying conformations (access, binding, and extrusion) during transport. Drugs are exported following an ordered conformational change in these three monomers, through a functional rotation mechanism coupled with the proton relay cycle in ion pairs, which is driven by proton translocation. Multidrug recognition is based on a multisite drug-binding mechanism, in which two voluminous multidrug-binding pockets in cell membrane exporters recognize a wide range of substrates as a result of permutations at numerous binding sites that are specific for the partial structures of substrate molecules. The voluminous multidrug-binding pocket may have numerous binding sites even for a single substrate, suggesting that substrates may move between binding sites during transport, an idea named as multisite-drug-oscillation hypothesis. This hypothesis is consistent with the apparently broad substrate specificity of cell membrane exporters and their highly efficient ejection of drugs from the cell. Substrates are transported through dual multidrug-binding pockets via the peristaltic motion of the substrate translocation channel. Although there are no clinically available inhibitors of bacterial multidrug exporters, efforts to develop inhibitors based on structural information are underway.

No MeSH data available.


Related in: MedlinePlus

AcrAB-TolC tripartite complex and the drug sweeping/extrusion mode-switching hypothesis. (A) Currently postulated structure of the tripartite complex. The TolC (brown) trimer is directly docked with AcrB (green) trimer and three AcrA (pink) monomers are attached to the side. (B) Drug sweeping/extrusion mode-switching hypothesis. (C) AcrB trimers switching between the symmetric resting stage (left) and the asymmetric active stage (right).
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Figure 13: AcrAB-TolC tripartite complex and the drug sweeping/extrusion mode-switching hypothesis. (A) Currently postulated structure of the tripartite complex. The TolC (brown) trimer is directly docked with AcrB (green) trimer and three AcrA (pink) monomers are attached to the side. (B) Drug sweeping/extrusion mode-switching hypothesis. (C) AcrB trimers switching between the symmetric resting stage (left) and the asymmetric active stage (right).

Mentions: Regarding AcrA, bi-partite AcrA-AcrB, and AcrA-TolC complexes are detected (Tikhonova and Zgurskaya, 2004; Touze et al., 2004), and AcrA is thought to recruit TolC to form a tripartite complex (Tikhonova et al., 2009). The AcrA structure has four domains: the α-hairpin, lipoyl, β-barrel, and MP (membrane proximal or β-roll) domains (Mikolosko et al., 2006; Symmons et al., 2009). Cross-linking between AcrA and AcrB showed a 1:1 stoichiometry (Symmons et al., 2009). AcrA-TolC cross linking (Lobedanz et al., 2007) and MexA-OprM (the P. aeruginosa homolog) cross linking (Ferrandez et al., 2012) also showed a 1:1 stoichiometry. Thus, the most likely model for the tripartite complex is that three AcrA molecules are attached to the TolC3-AcrB3 direct docking complex (Figure 13A) (Symmons et al., 2009). The α-hairpins of AcrA interact with TolC, and three other domains interact with the DN and PN2 domains of AcrB.


Structural basis of RND-type multidrug exporters.

Yamaguchi A, Nakashima R, Sakurai K - Front Microbiol (2015)

AcrAB-TolC tripartite complex and the drug sweeping/extrusion mode-switching hypothesis. (A) Currently postulated structure of the tripartite complex. The TolC (brown) trimer is directly docked with AcrB (green) trimer and three AcrA (pink) monomers are attached to the side. (B) Drug sweeping/extrusion mode-switching hypothesis. (C) AcrB trimers switching between the symmetric resting stage (left) and the asymmetric active stage (right).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4403515&req=5

Figure 13: AcrAB-TolC tripartite complex and the drug sweeping/extrusion mode-switching hypothesis. (A) Currently postulated structure of the tripartite complex. The TolC (brown) trimer is directly docked with AcrB (green) trimer and three AcrA (pink) monomers are attached to the side. (B) Drug sweeping/extrusion mode-switching hypothesis. (C) AcrB trimers switching between the symmetric resting stage (left) and the asymmetric active stage (right).
Mentions: Regarding AcrA, bi-partite AcrA-AcrB, and AcrA-TolC complexes are detected (Tikhonova and Zgurskaya, 2004; Touze et al., 2004), and AcrA is thought to recruit TolC to form a tripartite complex (Tikhonova et al., 2009). The AcrA structure has four domains: the α-hairpin, lipoyl, β-barrel, and MP (membrane proximal or β-roll) domains (Mikolosko et al., 2006; Symmons et al., 2009). Cross-linking between AcrA and AcrB showed a 1:1 stoichiometry (Symmons et al., 2009). AcrA-TolC cross linking (Lobedanz et al., 2007) and MexA-OprM (the P. aeruginosa homolog) cross linking (Ferrandez et al., 2012) also showed a 1:1 stoichiometry. Thus, the most likely model for the tripartite complex is that three AcrA molecules are attached to the TolC3-AcrB3 direct docking complex (Figure 13A) (Symmons et al., 2009). The α-hairpins of AcrA interact with TolC, and three other domains interact with the DN and PN2 domains of AcrB.

Bottom Line: Multidrug recognition is based on a multisite drug-binding mechanism, in which two voluminous multidrug-binding pockets in cell membrane exporters recognize a wide range of substrates as a result of permutations at numerous binding sites that are specific for the partial structures of substrate molecules.Substrates are transported through dual multidrug-binding pockets via the peristaltic motion of the substrate translocation channel.Although there are no clinically available inhibitors of bacterial multidrug exporters, efforts to develop inhibitors based on structural information are underway.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Cell Membrane Structural Biology, Institute of Scientific and Industrial Research, Osaka University Ibaraki, Japan.

ABSTRACT
Bacterial multidrug exporters are intrinsic membrane transporters that act as cellular self-defense mechanism. The most notable characteristics of multidrug exporters is that they export a wide range of drugs and toxic compounds. The overexpression of these exporters causes multidrug resistance. Multidrug-resistant pathogens have become a serious problem in modern chemotherapy. Over the past decade, investigations into the structure of bacterial multidrug exporters have revealed the multidrug recognition and export mechanisms. In this review, we primarily discuss RND-type multidrug exporters particularly AcrAB-TolC, major drug exporter in Gram-negative bacteria. RND-type drug exporters are tripartite complexes comprising a cell membrane transporter, an outer membrane channel and an adaptor protein. Cell membrane transporters and outer membrane channels are homo-trimers; however, there is no consensus on the number of adaptor proteins in these tripartite complexes. The three monomers of a cell membrane transporter have varying conformations (access, binding, and extrusion) during transport. Drugs are exported following an ordered conformational change in these three monomers, through a functional rotation mechanism coupled with the proton relay cycle in ion pairs, which is driven by proton translocation. Multidrug recognition is based on a multisite drug-binding mechanism, in which two voluminous multidrug-binding pockets in cell membrane exporters recognize a wide range of substrates as a result of permutations at numerous binding sites that are specific for the partial structures of substrate molecules. The voluminous multidrug-binding pocket may have numerous binding sites even for a single substrate, suggesting that substrates may move between binding sites during transport, an idea named as multisite-drug-oscillation hypothesis. This hypothesis is consistent with the apparently broad substrate specificity of cell membrane exporters and their highly efficient ejection of drugs from the cell. Substrates are transported through dual multidrug-binding pockets via the peristaltic motion of the substrate translocation channel. Although there are no clinically available inhibitors of bacterial multidrug exporters, efforts to develop inhibitors based on structural information are underway.

No MeSH data available.


Related in: MedlinePlus