Structure and efflux mechanism of the yeast pleiotropic drug resistance transporter Pdr5.
Smits, Sander HJ
Luisi, Ben F
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Harris, A., Wagner, M., Du, D., Raschka, S., Nentwig, L., Gohlke, H., Smits, S. H., et al. (2021). Structure and efflux mechanism of the yeast pleiotropic drug resistance transporter Pdr5.. Nature Communications, 12 (1), 5254-5254. https://doi.org/10.1038/s41467-021-25574-8
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.
ATP-Binding Cassette Transporters, Adenosine Triphosphate, Catalytic Domain, Cryoelectron Microscopy, Detergents, Drug Resistance, Fungal, Genetic Pleiotropy, Hydrolysis, Mutation, Protein Conformation, Protein Domains, Rhodamines, Saccharomyces cerevisiae Proteins, Vanadates
Open Access funding enabled and organized by Projekt DEAL.
European Research Council (742210)
Wellcome Trust (200873/Z/16/Z)
External DOI: https://doi.org/10.1038/s41467-021-25574-8
This record's URL: https://www.repository.cam.ac.uk/handle/1810/330379
Attribution 4.0 International
Licence URL: https://creativecommons.org/licenses/by/4.0/