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The homodimeric ATP‐binding cassette transporter LmrA mediates multidrug transport by an alternating two‐site (two‐cylinder engine) mechanism

The bacterial LmrA protein and the mammalian multidrug resistance P‐glycoprotein are closely related ATP‐binding cassette (ABC) transporters that confer multidrug resistance on cells by mediating the extrusion of drugs at the expense of ATP hydrolysis. The mechanisms by which transport is mediated, and by which ATP hydrolysis is coupled to drug transport, are not known. Based on equilibrium binding experiments, photoaffinity labeling and drug transport assays, we conclude that homodimeric LmrA mediates drug transport by an alternating two‐site transport (two‐cylinder engine) mechanism. The transporter possesses two drug‐binding sites: a transport‐competent site on the inner membrane surface and a drug‐release site on the outer membrane surface. The interconversion of these two sites, driven by the hydrolysis of ATP, occurs via a catalytic transition state intermediate in which the drug transport site is occluded. The mechanism proposed for LmrA may also be relevant for P‐glycoprotein and other ABC transporters.