DOI: 10.7554/elife.03145. 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

10.7554/elife.03145

Crossref journal-article

eLife Sciences Publications, Ltd

eLife (4374)

Abstract

Membrane transporters of the RND superfamily confer multidrug resistance to pathogenic bacteria, and are essential for cholesterol metabolism and embryonic development in humans. We use high-resolution X-ray crystallography and computational methods to delineate the mechanism of the homotrimeric RND-type proton/drug antiporter AcrB, the active component of the major efflux system AcrAB-TolC in Escherichia coli, and one most complex and intriguing membrane transporters known to date. Analysis of wildtype AcrB and four functionally-inactive variants reveals an unprecedented mechanism that involves two remote alternating-access conformational cycles within each protomer, namely one for protons in the transmembrane region and another for drugs in the periplasmic domain, 50 Å apart. Each of these cycles entails two distinct types of collective motions of two structural repeats, coupled by flanking α-helices that project from the membrane. Moreover, we rationalize how the cross-talk among protomers across the trimerization interface might lead to a more kinetically efficient efflux system.

Bibliography

Eicher, T., Seeger, M. A., Anselmi, C., Zhou, W., BrandstÃ¤tter, L., Verrey, F., Diederichs, K., Faraldo-GÃ³mez, J. D., & Pos, K. M. (2014). Coupling of remote alternating-access transport mechanisms for protons and substrates in the multidrug efflux pump AcrB. ELife, 3. CLOCKSS.

Authors 9

Thomas Eicher (first)
Markus A Seeger (additional)
Claudio Anselmi (additional)
Wenchang Zhou (additional)
Lorenz Brandstätter (additional)
François Verrey (additional)
Kay Diederichs (additional)
José D Faraldo-Gómez (additional)
Klaas M Pos (additional)

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Dates

Type	When
Created	10 years, 11 months ago (Sept. 9, 2014, 7:42 a.m.)
Deposited	1 year, 10 months ago (Oct. 11, 2023, 8:45 p.m.)
Indexed	4 weeks, 1 day ago (July 30, 2025, 1:08 p.m.)
Issued	10 years, 11 months ago (Sept. 19, 2014)
Published	10 years, 11 months ago (Sept. 19, 2014)
Published Online	10 years, 11 months ago (Sept. 19, 2014)

Funders 18

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Swiss National Science Foundation 10.13039/501100001711 Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
Region: Europe
pri (Trusts, charities, foundations (both public and private))
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German Research Foundation Collaborative Research Centre
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BibTeX

@article{Eicher_2014, title={Coupling of remote alternating-access transport mechanisms for protons and substrates in the multidrug efflux pump AcrB}, volume={3}, ISSN={2050-084X}, url={http://dx.doi.org/10.7554/elife.03145}, DOI={10.7554/elife.03145}, journal={eLife}, publisher={eLife Sciences Publications, Ltd}, 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 D and Pos, Klaas M}, year={2014}, month=sep }

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  "abstract": "<jats:p>Membrane transporters of the RND superfamily confer multidrug resistance to pathogenic bacteria, and are essential for cholesterol metabolism and embryonic development in humans. We use high-resolution X-ray crystallography and computational methods to delineate the mechanism of the homotrimeric RND-type proton/drug antiporter AcrB, the active component of the major efflux system AcrAB-TolC in Escherichia coli, and one most complex and intriguing membrane transporters known to date. Analysis of wildtype AcrB and four functionally-inactive variants reveals an unprecedented mechanism that involves two remote alternating-access conformational cycles within each protomer, namely one for protons in the transmembrane region and another for drugs in the periplasmic domain, 50 \u00c5 apart. Each of these cycles entails two distinct types of collective motions of two structural repeats, coupled by flanking \u03b1-helices that project from the membrane. Moreover, we rationalize how the cross-talk among protomers across the trimerization interface might lead to a more kinetically efficient efflux system.</jats:p>",
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  "title": "Coupling of remote alternating-access transport mechanisms for protons and substrates in the multidrug efflux pump AcrB",
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      "given": "Thomas",
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