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


Type
Article
Change log
Authors
Wagner, Manuel 
Du, Dijun 
Raschka, Stefanie 
Nentwig, Lea-Marie 
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.

Description
Keywords
Vanadates, Rhodamines, ATP-Binding Cassette Transporters, Saccharomyces cerevisiae Proteins, Adenosine Triphosphate, Detergents, Cryoelectron Microscopy, Drug Resistance, Fungal, Catalytic Domain, Protein Conformation, Hydrolysis, Mutation, Genetic Pleiotropy, Protein Domains
Journal Title
Nature communications
Conference Name
Journal ISSN
2041-1723
Volume Title
12
Publisher
Sponsorship
European Research Council (742210)