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Coupling of remote alternating-access transport mechanisms for protons and substrates in the multidrug efflux pump AcrB

Coupling of remote alternating-access transport mechanisms for protons and substrates in the multidrug efflux pump AcrB

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EICHER, Thomas, Markus A. SEEGER, Claudio ANSELMI, Wenchang ZHOU, Lorenz BRANDSTÄTTER, François VERREY, Kay DIEDERICHS, José FARALDO-GÓMEZ, Klaas M. POS, 2014. Coupling of remote alternating-access transport mechanisms for protons and substrates in the multidrug efflux pump AcrB. In: eLife. 3, e03145. eISSN 2050-084X. Available under: doi: 10.7554/eLife.03145

@article{Eicher2014Coupl-29321, title={Coupling of remote alternating-access transport mechanisms for protons and substrates in the multidrug efflux pump AcrB}, year={2014}, doi={10.7554/eLife.03145}, volume={3}, journal={eLife}, author={Eicher, Thomas and Seeger, Markus A. and Anselmi, Claudio and Zhou, Wenchang and Brandstätter, Lorenz and Verrey, François and Diederichs, Kay and Faraldo-Gómez, José and Pos, Klaas M.}, note={Article Number: e03145} }

Zhou, Wenchang eng Seeger, Markus A. Coupling of remote alternating-access transport mechanisms for protons and substrates in the multidrug efflux pump AcrB Brandstätter, Lorenz Verrey, François Seeger, Markus A. Anselmi, Claudio Eicher, Thomas Zhou, Wenchang Diederichs, Kay Diederichs, Kay Faraldo-Gómez, José Brandstätter, Lorenz Faraldo-Gómez, José Pos, Klaas M. Pos, Klaas M. Eicher, Thomas Anselmi, Claudio Verrey, François 2014 2014-11-27T09:22:33Z 2014-11-27T09:22:33Z The interior of living cells is separated from their external environment by an enveloping membrane that serves as a protective barrier. To regulate the chemical composition of their interior, cells are equipped with specialized proteins in their membranes that move substances in and out of cells. Membrane proteins that expel molecules from the inside to the outside of the cell are called efflux pumps.<br /><br />In Escherichia coli bacteria, an efflux pump known as AcrB is part of a system that removes toxic substances from the bacterial cell—such as the antibiotics used to treat bacterial infections. AcrB and other closely related efflux pumps in pathogenic bacteria are often polyspecific transporters—they can transport a large number of different toxic molecules. These efflux pump systems are also more active in bacteria that have been targeted by antibiotics, and therefore they help bacteria to evolve resistance to multiple drugs. The emergence of bacterial multi-drug resistance is a global threat to human health; to combat this phenomenon, it is essential to understand its molecular basis.<br /><br />Each AcrB protein has three main parts or domains. The periplasmic domain, which is located between the two membranes that surround E. coli, works via an ‘alternating-access cycle’; that is, the shape of the periplasmic domain changes between three different forms in such a way that antibiotic molecules are first captured and subsequently squeezed through the protein towards the outside of the cell. However, the mechanism of the transmembrane domain—which is embedded in the innermost membrane of the bacterium and is the source of energy for the transport process—was not understood.<br /><br />Here, Eicher et al. use X-ray crystallography to examine the three-dimensional structures of the AcrB efflux pump—and several inactive variants—in high detail. Combining these results with computer simulations reveals the mechanism used by the transmembrane domain to take up protons from the exterior and transport them into the cell. Proton transport also proceeds according to an alternating-access mechanism—and, although the transmembrane and periplasmic domains are far apart, their movements are tightly linked. Thus, because proton uptake releases energy, the transmembrane domain effectively powers the periplasmic domain to expel drugs and other molecules. Eicher et al. note that a similar mechanism has not been seen before in other efflux pumps or transporter proteins.<br /><br />Understanding how AcrB works opens up new avenues that could be exploited to develop new drugs against multidrug resistant bacteria. Furthermore, Eicher et al. suggest that efflux pumps in humans closely related to AcrB might function in a similar way—including those required for regulation of cellular cholesterol, and for the correct development of embryos.

Dateiabrufe seit 27.11.2014 (Informationen über die Zugriffsstatistik)

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