4U8Y

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

(2014) Elife 3: e03145

• PubMed: 25248080 Search on PubMedSearch on PubMed Central
• DOI: https://doi.org/10.7554/eLife.03145
• Primary Citation of Related Structures:  
  4U8V, 4U8Y, 4U95, 4U96


• PubMed 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.

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Organizational Affiliation: 

Institute of Biochemistry, Goethe University, Frankfurt am Main, Germany.