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bioRxiv · 10.1101/2021.02.09.430491

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

Harris, A.·Wagner, M.·Du, D.·Raschka, S.·Gohlke, H.·Smits, S. H. J.·Luisi, B. F.·Schmitt, L.
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Abstract

Pdr5, a member of the extensive ABC transporter superfamily, is representative of a clinically relevant subgroup involved in pleiotropic drug resistance. Through the coupling of nucleotide hydrolysis with drug efflux, Pdr5 homologues enable pathogenic species to survive in the presence of chemically diverse antifungal agents. Our structural and functional results reveal 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 interdomain interfaces to support a peristaltic motion of the pumped molecule. The efflux model proposed here rationalises the pleiotropic impact of Pdr5 and opens avenues for the development of effective antifungal compounds.

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Harris, A., Wagner, M., Du, D., Raschka, S., Gohlke, H., Smits, S. H. J., Luisi, B. F., Schmitt, L.. 2021-02-09. Structure and efflux mechanism of the yeast pleiotropic drug resistance transporter Pdr5. https://doi.org/10.1101/2021.02.09.430491

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