The multidrug transporter Pdr5: a molecular diode?

Abstract

A subset of the family of ATP-binding cassette (ABC) transporters has been in focus owing to their involvement in conferring multidrug resistance in cancer cells and among immune compromised individuals. Saccharomyces cerevisiae is protected against xenobiotics by similar machineries that are part of the pleitropic drug resistance (PDR) network. The ABC transporter Pdr5 is an important member of this PDR network in yeast and is involved in cellular detoxification by the efflux of a wide variety of drugs and substrates. In this review, we focus on the aspects of detergent effects and the degeneracy in conserved sequences that is observed in the nucleotide binding domains of Pdr5 and discuss their functional relevance.

Evidence for a Molecular Diode-based Mechanism in a Multispecific ATP-binding cassette (ABC) Exporter

“…The most appealing model that accords with our data is that this residue helps create a molecular diode or one-way gate in Pdr5 (15). According to this model, multidrug efflux pumps evolved a mechanism to avoid undesired reuptake of a drug that has just been transported.…”

“…We photo-cross-linked the samples for 10 min with 365-nm UV light in an ice water bath, followed by electrophoresis on 7% NuPAGE gels (Invitrogen). We quantified the gels as described previously (15). We also exposed the dried gels to x-ray film to create an autoradiogram of the samples.…”

“…Gupta et al (15) proposed that a failure of drug release hinders the conformational freedom of the transporter which is locked in an outward facing conformation. As a consequence, nucleotide exchange is impaired, resulting in reduced ATPase activity.…”

Insight into Pleiotropic Drug Resistance ATP-binding Cassette Pump Drug Transport through Mutagenesis of Cdr1p Transmembrane Domains*

“…The NBDs bind and hydrolyze the ATP that powers drug efflux. Conformational changes induced by ATP binding and/or hydrolysis are transmitted from the NBDs to the TMDs, which can result in drug translocation, drug efflux, or resetting of the reaction cycle (16).…”

ATP binding cassette systems: structures, mechanisms, and functions

“…Together, these results suggest a similar architecture in other eukaryotic ABC exporters, at least those belonging to subfamilies B and C. However, the functional P-glycoprotein homologue Pdr5p conferring pleiotropic drug resistance (PDR) in yeast differs significantly in sequence and architecture. Consisting of degenerated NBDs and an inverted topology (NBD-TMD-NBD-TMD), Pdr5p is a non-canonical ABC transporter that exhibits only basal ATPase activity, which, in contrast to MDR1, is not stimulated by the tested substrates [26].…”