Structure and efflux mechanism of the yeast pleiotropic drug resistance transporter Pdr5

Andrzej Harris, Manuel Wagner, Dijun Du, Stefanie Raschka, Lea-Marie Nentwig, Holger Gohlke, Sander H. J. Smits, Ben F. Luisi () and Lutz Schmitt ()
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Andrzej Harris: University of Cambridge
Manuel Wagner: Heinrich Heine University Düsseldorf, Universitätsstraße 1
Dijun Du: University of Cambridge
Stefanie Raschka: Heinrich Heine University Düsseldorf, Universitätsstraße 1
Lea-Marie Nentwig: Heinrich Heine University Düsseldorf, Universitätsstraße 1
Holger Gohlke: Heinrich Heine University Düsseldorf, Universitätsstraße 1
Sander H. J. Smits: Heinrich Heine University Düsseldorf, Universitätsstraße 1
Ben F. Luisi: University of Cambridge
Lutz Schmitt: Heinrich Heine University Düsseldorf, Universitätsstraße 1

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: Abstract Pdr5, a member of the extensive ABC transporter superfamily, is representative of a clinically relevant subgroup involved in pleiotropic drug resistance. Pdr5 and its homologues drive drug efflux through uncoupled hydrolysis of nucleotides, enabling organisms such as baker’s yeast and pathogenic fungi to survive in the presence of chemically diverse antifungal agents. Here, we present the molecular structure of Pdr5 solved with single particle cryo-EM, revealing details of an ATP-driven conformational cycle, which mechanically drives drug translocation through an amphipathic channel, and a clamping switch within a conserved linker loop that acts as a nucleotide sensor. One half of the transporter remains nearly invariant throughout the cycle, while its partner undergoes changes that are transmitted across inter-domain interfaces to support a peristaltic motion of the pumped molecule. The efflux model proposed here rationalises the pleiotropic impact of Pdr5 and opens new avenues for the development of effective antifungal compounds.

Date: 2021
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DOI: 10.1038/s41467-021-25574-8

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