It's a depressingly familiar scenario. You have the right drug for the right target, you know how to deliver it to the right group of cells, but then you find that those same cells have developed resistance to the drug. The commonest cause of such 'multidrug' resistance (MDR) — which is being increasingly observed for antibiotics and anticancer drugs — is a family of transporter proteins that use the energy derived from hydrolysing ATP to pump drugs out of cells. Because proteins of this type share the common structural feature of an ATP-binding cassette (ABC), they are known as MDR–ABC transporters. Now, for the first time, Chang and Roth report the high-resolution X-ray structure of one of the 50 or so members of this protein class, the bacterial transporter Eco-msbA.

Eco-msbA is the closest bacterial homologue of the most studied human MDR–ABC transporter, P-glycoprotein, and prevents lethal accumulations of lipid A building up on the cytoplasmic face of the cell membrane in Escherichia coli. Chang and Roth's data indicate that Eco-msbA functions as a homodimer, with the two protein molecules interfacing in the outer membrane to form an inverted 'V' in the cell's lipid bilayer. The two ABC elements are cytoplasmic, as expected, and the two angled transmembrane domains form a chamber, which is closed at the top. The authors propose that, upon ABC activation, a conformational change leads hydrophobic lipid A to be carried into the lower part of the chamber by a substrate-specific binding site. Lipid A is then 'flipped' into the upper part by unfavourable electrostatic interactions in the chamber, before being translocated back into the outer cell membrane and out of the cell. Eco-msbA is therefore not a pore through the cell membrane, but a molecular machine.

Despite structural and functional similarities throughout the family, other MDR–ABC transporters — particularly those that transport hydrophilic substrates — could function differently. But importantly, we now have a snapshot of how some of these proteins might look.