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

Nat Commun. 2021 Sep 6;12(1):5254. doi: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP-Binding Cassette Transporters / chemistry*
  • ATP-Binding Cassette Transporters / genetics
  • ATP-Binding Cassette Transporters / metabolism*
  • Adenosine Triphosphate / metabolism
  • Catalytic Domain
  • Cryoelectron Microscopy
  • Detergents / chemistry
  • Drug Resistance, Fungal / genetics
  • Genetic Pleiotropy
  • Hydrolysis
  • Mutation
  • Protein Conformation
  • Protein Domains
  • Rhodamines / chemistry
  • Rhodamines / metabolism
  • Saccharomyces cerevisiae Proteins / chemistry*
  • Saccharomyces cerevisiae Proteins / genetics
  • Saccharomyces cerevisiae Proteins / metabolism*
  • Vanadates / chemistry
  • Vanadates / metabolism


  • ATP-Binding Cassette Transporters
  • Detergents
  • PDR5 protein, S cerevisiae
  • Rhodamines
  • Saccharomyces cerevisiae Proteins
  • rhodamine 6G
  • Vanadates
  • Adenosine Triphosphate