4U95: Coupling Of Remote Alternating-access Transport Mechanisms For Protons And Substrates In The Multidrug Efflux Pump Acrb

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 A apart. Each of these cycles entails two distinct types of collective motions of two structural repeats, coupled by flanking alpha-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.
PDB ID: 4U95Download
MMDB ID: 123909
PDB Deposition Date: 2014/8/5
Updated in MMDB: 2014/10
Experimental Method:
x-ray diffraction
Resolution: 2  Å
Source Organism:
Escherichia coli K-12
Similar Structures:
Biological Unit for 4U95: pentameric; determined by author and by software (PISA)
Molecular Components in 4U95
Label Count Molecule
Proteins (5 molecules)
Multidrug Efflux Pump Subunit Acrb(Gene symbol: acrB)
Molecule annotation
Molecule annotation
Chemicals (4 molecules)
* Click molecule labels to explore molecular sequence information.

Citing MMDB