1. Department of Cell Membrane Biology, Institute of Scientific and Industrial Research, Osaka University, Ibaraki, Osaka 567-0047, Japan
2. PRESTO, and
3. CREST, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan
4. Faculty of Pharmaceutical Science, and
5. Institute for Protein Research, Osaka University, Suita, Osaka 565-0871, Japan
6. SOSHO Inc., Hommachi, Osaka 541-0053, Japan

Correspondence to: Satoshi Murakami^1,2,3,4,6 Correspondence and requests for materials should be addressed to S.M. (Email: mura@sanken.osaka-u.ac.jp). Coordinates for the unliganded, AcrB–minocycline complex and AcrB–doxorubicin complex structures have been deposited in the Protein Data Bank under accession numbers 2DHH, 2DRD and 2DR6, respectively.

Abstract

AcrB is a principal multidrug efflux transporter in Escherichia coli that cooperates with an outer-membrane channel, TolC, and a membrane-fusion protein, AcrA. Here we describe crystal structures of AcrB with and without substrates. The AcrB–drug complex consists of three protomers, each of which has a different conformation corresponding to one of the three functional states of the transport cycle. Bound substrate was found in the periplasmic domain of one of the three protomers. The voluminous binding pocket is aromatic and allows multi-site binding. The structures indicate that drugs are exported by a three-step functionally rotating mechanism in which substrates undergo ordered binding change.

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