Drug export pathway of multidrug exporter AcrB revealed by DARPin inhibitors.
The multidrug exporter AcrB is the inner membrane component of the AcrAB-TolC drug efflux system in Escherichia coli and is responsible for the resistance of this organism to a wide range of drugs. Here we describe the crystal structure of the trimeric AcrB in complex with a designed ankyrin-repeat protein (DARPin) inhibitor at 2.5-A resolution. The three subunits of AcrB are locked in different conformations revealing distinct channels in each subunit. There seems to be remote conformational coupling between the channel access, exit, and the putative proton-translocation site, explaining how the proton motive force is used for drug export. Thus our structure suggests a transport pathway not through the central pore but through the identified channels in the individual subunits, which greatly advances our understanding of the multidrug export mechanism.
Sennhauser
Gaby
G
University of Zurich, Zurich, Switzerland.
Amstutz
Patrick
P
Briand
Christophe
C
Storchenegger
Otso
O
Grütter
Markus G
MG
D017089:Ankyrin Repeat / Q000502:physiology*; D001692:Biological Transport / Q000502:physiology; D018360:Crystallography, X-Ray; D024901:Drug Resistance, Multiple, Bacterial / Q000502:physiology; D029968:Escherichia coli Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding / Q000502:physiology; D011487:Protein Conformation; D017510:Protein Folding; D021122:Protein Subunits / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D018892:Proton-Motive Force / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*
D029968:Escherichia coli Proteins; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D046912:Multiprotein Complexes; D021122:Protein Subunits; C083496:AcrB protein, E coli