Allosteric drug transport mechanism of multidrug transporter AcrB

Heng-Keat Tam (), Wuen Ee Foong, Christine Oswald, Andrea Herrmann, Hui Zeng and Klaas M. Pos ()
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Heng-Keat Tam: Institute of Biochemistry, Goethe-University Frankfurt
Wuen Ee Foong: Institute of Biochemistry, Goethe-University Frankfurt
Christine Oswald: Institute of Biochemistry, Goethe-University Frankfurt
Andrea Herrmann: Institute of Biochemistry, Goethe-University Frankfurt
Hui Zeng: Institute of Biochemistry, Goethe-University Frankfurt
Klaas M. Pos: Institute of Biochemistry, Goethe-University Frankfurt

Nature Communications, 2021, vol. 12, issue 1, 1-10

Abstract: Abstract Gram-negative bacteria maintain an intrinsic resistance mechanism against entry of noxious compounds by utilizing highly efficient efflux pumps. The E. coli AcrAB-TolC drug efflux pump contains the inner membrane H+/drug antiporter AcrB comprising three functionally interdependent protomers, cycling consecutively through the loose (L), tight (T) and open (O) state during cooperative catalysis. Here, we present 13 X-ray structures of AcrB in intermediate states of the transport cycle. Structure-based mutational analysis combined with drug susceptibility assays indicate that drugs are guided through dedicated transport channels toward the drug binding pockets. A co-structure obtained in the combined presence of erythromycin, linezolid, oxacillin and fusidic acid shows binding of fusidic acid deeply inside the T protomer transmembrane domain. Thiol cross-link substrate protection assays indicate that this transmembrane domain-binding site can also accommodate oxacillin or novobiocin but not erythromycin or linezolid. AcrB-mediated drug transport is suggested to be allosterically modulated in presence of multiple drugs.

Date: 2021
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DOI: 10.1038/s41467-021-24151-3

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