TY  - JOUR
AU  - Harris, Andrzej
AU  - Wagner, Manuel
AU  - Du, Dijun
AU  - Raschka, Stefanie
AU  - Nentwig, Lea-Marie
AU  - Gohlke, Holger
AU  - Smits, Sander H. J.
AU  - Luisi, Ben F.
AU  - Schmitt, Lutz
TI  - Structure and efflux mechanism of the yeast pleiotropic drug resistance transporter Pdr5
JO  - Nature Communications
VL  - 12
IS  - 1
SN  - 2041-1723
CY  - [London]
PB  - Nature Publishing Group UK
M1  - FZJ-2021-03425
SP  - 5254
PY  - 2021
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:34489436
UR  - <Go to ISI:>//WOS:000694666900027
DO  - DOI:10.1038/s41467-021-25574-8
UR  - https://juser.fz-juelich.de/record/894854
ER  -