Journal Article

FZJ-2021-03425

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Structure and efflux mechanism of the yeast pleiotropic drug resistance transporter Pdr5

Harris, A. ; Wagner, M. ; Du, D. ; Raschka, S. ; Nentwig, L.-M. ; Gohlke, H.FZJ* ; Smits, S. H. J. ; Luisi, B. F. (Corresponding author) ; Schmitt, L. (Corresponding author)

2021
Nature Publishing Group UK [London]

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Please use a persistent id in citations: http://hdl.handle.net/2128/28628  doi:10.1038/s41467-021-25574-8

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.

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Contributing Institute(s):

1. Jülich Supercomputing Center (JSC)
2. John von Neumann - Institut für Computing (NIC)
3. Strukturbiochemie (IBI-7)
4. Bioinformatik (IBG-4)

Research Program(s):

1. 5111 - Domain-Specific Simulation Data Life Cycle Labs (SDLs) and Research Groups (POF4-511) (POF4-511)
2. 2171 - Biological and environmental resources for sustainable use (POF4-217) (POF4-217)
3. 2172 - Utilization of renewable carbon and energy sources and engineering of ecosystem functions (POF4-217) (POF4-217)
4. Forschergruppe Gohlke (hkf7_20200501) (hkf7_20200501)
5. DFG project 417919780 - Zentrum für strukturelle Studien (417919780)

Appears in the scientific report 2021

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