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

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  Publication Details (including relevant citation   information):

  T Eicher, MA Seeger, C Anselmi, W Zhou, L Brandstätter, F Verrey,   K Diederichs, JD Faraldo-Gómez & KM Pos. eLife 3 (2014)   e03145


  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.

  Address (URL): http://www.ncbi.nlm.nih.gov/pubmed/25248080