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.
journal_name
Elifejournal_title
eLifeauthors
Eicher T,Seeger MA,Anselmi C,Zhou W,Brandstätter L,Verrey F,Diederichs K,Faraldo-Gómez JD,Pos KMdoi
10.7554/eLife.03145subject
Has Abstractpub_date
2014-09-19 00:00:00issn
2050-084Xjournal_volume
3pub_type
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