TITLE: The AcrB Efflux Pump: a Triple-Barrel Shotgun for Getting Rid of Drugs

SPEAKER: Professor Edward Yu,

TIME: Thursday Oct. 27, 2005 at 4 PM

PLACE: George P. Williams, Jr. Lecture Hall, (Olin 101)

Multidrug efflux pumps interfere significantly with cancer chemotherapy and the treatment of bacterial infections, by recognizing a number of structurally unrelated toxic compounds and actively extruding them from cells. We have determined the x-ray structures of the Escherichia coli AcrB transmembrane efflux pump in the presence of four structurally different agents. These are the first structures of any transporter that have been solved in complex with a variety of ligands by x-ray crystallography. The crystal structures illustrate that three ligand molecules 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 subsequent study of the efflux pump by crystallizing a mutant AcrB with five structurally diverse ligands indicates that AcrB consists of two distinct binding sites. These five ligands not only bind to various positions of the central cavity, but also to residues lining the deep external depression formed by the C-terminal periplasmic domain. The structures also suggest that AcrB assembles as a trimer of three identical channels for the extrusion of drugs. We recently collected the x-ray diffraction data of a co-crystal of AcrB with a periplasmic membrane fusion protein, AcrA. The data strongly support the hypothesis that these two efflux proteins form a complex in the periplasm, and assist each other for drug transport.

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