Structural basis of multiple drug-binding capacity of the AcrB multidrug efflux pump.
Multidrug efflux pumps cause serious problems in cancer chemotherapy and treatment of bacterial infections. Yet high-resolution structures of ligand transporter complexes have previously been unavailable. We obtained x-ray crystallographic structures of the trimeric AcrB pump from Escherichia coli with four structurally diverse ligands. The structures show that three molecules of ligands bind simultaneously to the extremely large central cavity of 5000 cubic angstroms, primarily by hydrophobic, aromatic stacking and van der Waals interactions. Each ligand uses a slightly different subset of AcrB residues for binding. The bound ligand molecules often interact with each other, stabilizing the binding.
Yu
Edward W
EW
Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720-3202, USA.
McDermott
Gerry
G
Zgurskaya
Helen I
HI
Nikaido
Hiroshi
H
Koshland
Daniel E
DE
D000890:Anti-Infective Agents / Q000737:chemistry / Q000378:metabolism; D000891:Anti-Infective Agents, Local / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D002352:Carrier Proteins / Q000737:chemistry* / Q000302:isolation & purification / Q000378:metabolism*; D002462:Cell Membrane / Q000737:chemistry; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D002939:Ciprofloxacin / Q000737:chemistry / Q000378:metabolism; D003460:Crystallization; D018360:Crystallography, X-Ray; D003868:Dequalinium / Q000737:chemistry / Q000378:metabolism; D029968:Escherichia coli Proteins / Q000737:chemistry* / Q000302:isolation & purification / Q000378:metabolism*; D004996:Ethidium / Q000737:chemistry / Q000378:metabolism; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D008565:Membrane Proteins / Q000737:chemistry* / Q000302:isolation & purification / Q000378:metabolism*; D008958:Models, Molecular; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011485:Protein Binding; D011487:Protein Conformation; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D012235:Rhodamines / Q000737:chemistry / Q000378:metabolism; D055672:Static Electricity
D000890:Anti-Infective Agents; D000891:Anti-Infective Agents, Local; D002352:Carrier Proteins; D002939:Ciprofloxacin; D003868:Dequalinium; D029968:Escherichia coli Proteins; D004996:Ethidium; D008024:Ligands; D008565:Membrane Proteins; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D012235:Rhodamines; C083496:AcrB protein, E coli