The role of the degenerate nucleotide binding site in type I ABC exporters

Stockner, Thomas; Gradisch, Ralph; Schmitt, Lutz

doi:10.1002/1873-3468.13997

Cited by 43 publications

(93 citation statements)

References 162 publications

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“…In this state, corresponding to our ADP-Pdr5 model, the transporter has an ADP molecule in NBS2 and ATP in the deviant NBS1. On the basis of cellular concentrations of ATP in S. cerevisiae (1.51 ± 0.32 mM (52)) and the transporter's KM for the nucleotide (1.7 to 1.9 mM in vivo 12,44 , 0.44 ± 0.05 mM in vitro (14)), it seems likely that the apo state may represent about 50% of the population. The other Pdr5 states, which were prepared from samples with added ATP, have the nucleotide bound in the non-catalytic, deviant binding site; this would support earlier suggestions that ATP remains in the site throughout the transport cycle (32) under physiological conditions.…”

Section: Drug Efflux Occurs As Pdr5 Switches Between Inward-and Outwamentioning

confidence: 99%

“…In Pdr5, one of the NBS is catalytically active (NBS2), while the other (NBS1) is inactive due to multiple substitutions in crucial residues of all but one motif. While this asymmetry is shared with many other ABC transporters (e.g., CFTR) ( 12 ), the PDR subfamily represents the most extreme case ( 13 ). It is unclear how ATPase-deficiency at this nucleotide-binding site supports the transport process.…”

Section: Introductionmentioning

confidence: 99%

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

Harris

Wagner

et al. 2021

Preprint

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Pdr5, a member of the extensive ABC transporter superfamily, is representative of a clinically relevant subgroup involved in pleiotropic drug resistance. Through the coupling of nucleotide hydrolysis with drug efflux, Pdr5 homologues enable pathogenic species to survive in the presence of chemically diverse antifungal agents. Our structural and functional results reveal 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 avenues for the development of effective antifungal compounds.

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Section: Drug Efflux Occurs As Pdr5 Switches Between Inward-and Outwamentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Harris

Wagner

et al. 2021

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…In Pdr5, one of the NBS is catalytically active (NBS2), while the other (NBS1) is inactive due to multiple substitutions in crucial residues of all but one motif. While this asymmetry is shared with many other ABC transporters (e.g., CFTR) 12 , the PDR subfamily represents its most extreme case 13 . It is unclear how ATPase-deficiency at this nucleotide-binding site supports the transport process.…”

Section: Introductionmentioning

confidence: 99%

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

Harris

Wagner

et al. 2021

Nat Commun

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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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“…In the first NBD of PDR transporters, the glutamine (Q) in the Q-loop is replaced by glutamate (E), the Pro-loop disappeared and histidine (H) in the H-loop is substituted by tyrosine (Y). Hence, the notion emerged that fungal PDRs would follow an asymmetric catalytic cycle [ 173 , 216 , 306 , 329 , 330 ].…”

Section: Key Residues and Motifs Are Conserved In Multidrug Transporters Abcg/pdrmentioning

confidence: 99%

Multidrug Resistance in Mammals and Fungi—From MDR to PDR: A Rocky Road from Atomic Structures to Transport Mechanisms

Khunweeraphong

Kuchler

2021

IJMS

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Multidrug resistance (MDR) can be a serious complication for the treatment of cancer as well as for microbial and parasitic infections. Dysregulated overexpression of several members of the ATP-binding cassette transporter families have been intimately linked to MDR phenomena. Three paradigm ABC transporter members, ABCB1 (P-gp), ABCC1 (MRP1) and ABCG2 (BCRP) appear to act as brothers in arms in promoting or causing MDR in a variety of therapeutic cancer settings. However, their molecular mechanisms of action, the basis for their broad and overlapping substrate selectivity, remains ill-posed. The rapidly increasing numbers of high-resolution atomic structures from X-ray crystallography or cryo-EM of mammalian ABC multidrug transporters initiated a new era towards a better understanding of structure–function relationships, and for the dynamics and mechanisms driving their transport cycles. In addition, the atomic structures offered new evolutionary perspectives in cases where transport systems have been structurally conserved from bacteria to humans, including the pleiotropic drug resistance (PDR) family in fungal pathogens for which high resolution structures are as yet unavailable. In this review, we will focus the discussion on comparative mechanisms of mammalian ABCG and fungal PDR transporters, owing to their close evolutionary relationships. In fact, the atomic structures of ABCG2 offer excellent models for a better understanding of fungal PDR transporters. Based on comparative structural models of ABCG transporters and fungal PDRs, we propose closely related or even conserved catalytic cycles, thus offering new therapeutic perspectives for preventing MDR in infectious disease settings.

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The role of the degenerate nucleotide binding site in type I ABC exporters

Cited by 43 publications

References 162 publications

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

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

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

Multidrug Resistance in Mammals and Fungi—From MDR to PDR: A Rocky Road from Atomic Structures to Transport Mechanisms

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