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

2013 ◽  
Vol 288 (34) ◽  
pp. 24480-24493 ◽  
Author(s):  
Manpreet Kaur Rawal ◽  
Mohammad Firoz Khan ◽  
Khyati Kapoor ◽  
Neha Goyal ◽  
Sobhan Sen ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Drug Transport ◽  
Transmembrane Domains ◽  
Atp Binding ◽  
Pleiotropic Drug Resistance ◽  
Insight Into ◽  
Atp Binding Cassette

scholarly journals A Member of the PLEIOTROPIC DRUG RESISTANCE Family of ATP Binding Cassette Transporters Is Required for the Formation of a Functional Cuticle in Arabidopsis

2011 ◽  
Vol 23 (5) ◽  
pp. 1958-1970 ◽  
Author(s):  
Michael Bessire ◽  
Sandra Borel ◽  
Guillaume Fabre ◽  
Luis Carraça ◽  
Nadia Efremova ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Atp Binding ◽  
Pleiotropic Drug Resistance ◽  
Atp Binding Cassette Transporters ◽  
Atp Binding Cassette

scholarly journals Genetic Separation of FK506 Susceptibility and Drug Transport in the Yeast Pdr5 ATP-binding Cassette Multidrug Resistance Transporter

1998 ◽  
Vol 9 (2) ◽  
pp. 523-543 ◽  
Author(s):  
Ralf Egner ◽  
Friederike E. Rosenthal ◽  
Anastasia Kralli ◽  
Dominique Sanglard ◽  
Karl Kuchler
Keyword(s):  
Drug Resistance ◽  
Substrate Specificity ◽  
Drug Transport ◽  
Transmembrane Domain ◽  
Substrate Recognition ◽  
Yeast Cells ◽  
Atp Binding ◽  
In Vitro Mutagenesis ◽  
Atp Binding Cassette Transporter ◽  
Atp Binding Cassette

Overexpression of the yeast Pdr5 ATP-binding cassette transporter leads to pleiotropic drug resistance to a variety of structurally unrelated cytotoxic compounds. To identify Pdr5 residues involved in substrate recognition and/or drug transport, we used a combination of random in vitro mutagenesis and phenotypic screening to isolate novel mutant Pdr5 transporters with altered substrate specificity. A plasmid library containing randomly mutagenized PDR5 genes was transformed into appropriate drug-sensitive yeast cells followed by phenotypic selection of Pdr5 mutants. Selected mutant Pdr5 transporters were analyzed with respect to their expression levels, subcellular localization, drug resistance profiles to cycloheximide, rhodamines, antifungal azoles, steroids, and sensitivity to the inhibitor FK506. DNA sequencing of six PDR5 mutant genes identified amino acids important for substrate recognition, drug transport, and specific inhibition of the Pdr5 transporter. Mutations were found in each nucleotide-binding domain, the transmembrane domain 10, and, most surprisingly, even in predicted extracellular hydrophilic loops. At least some point mutations identified appear to influence folding of Pdr5, suggesting that the folded structure is a major substrate specificity determinant. Surprisingly, a S1360F exchange in transmembrane domain 10 not only caused limited substrate specificity, but also abolished Pdr5 susceptibility to inhibition by the immunosuppressant FK506. This is the first report of a mutation in a yeast ATP-binding cassette transporter that allows for the functional separation of substrate transport and inhibitor susceptibility.

scholarly journals Regulation of Transcription Factor Pdr1p Function by an Hsp70 Protein in Saccharomyces cerevisiae

1998 ◽  
Vol 18 (3) ◽  
pp. 1147-1155 ◽  
Author(s):  
Timothy C. Hallstrom ◽  
David J. Katzmann ◽  
Rodrigo J. Torres ◽  
W. John Sharp ◽  
W. Scott Moye-Rowley
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Drug Resistance ◽  
Transcription Factor ◽  
Regulatory Protein ◽  
Atp Binding ◽  
Regulation Of Transcription ◽  
Pleiotropic Drug Resistance ◽  
Atp Binding Cassette Transporter ◽  
Encoding Genes ◽  
Atp Binding Cassette

ABSTRACT Multiple or pleiotropic drug resistance in the yeastSaccharomyces cerevisiae requires the expression of several ATP binding cassette transporter-encoding genes under the control of the zinc finger-containing transcription factor Pdr1p. The ATP binding cassette transporter-encoding genes regulated by Pdr1p include PDR5 and YOR1, which are required for normal cycloheximide and oligomycin tolerances, respectively. We have isolated a new member of the PDR gene family that encodes a member of the Hsp70 family of proteins found in this organism. This gene has been designated PDR13 and is required for normal growth. Overexpression of Pdr13p leads to an increase in both the expression of PDR5 and YOR1 and a corresponding enhancement in drug resistance. Pdr13p requires the presence of both the PDR1 structural gene and the Pdr1p binding sites in target promoters to mediate its effect on drug resistance and gene expression. A dominant, gain-of-function mutant allele ofPDR13 was isolated and shown to have the same phenotypic effects as when the gene is present on a 2μm plasmid. Genetic and Western blotting experiments indicated that Pdr13p exerts its effect on Pdr1p at a posttranslational step. These data support the view that Pdr13p influences pleiotropic drug resistance by enhancing the function of the transcriptional regulatory protein Pdr1p.

scholarly journals Ribosome protection by antibiotic resistance ATP-binding cassette protein

2018 ◽  
Vol 115 (20) ◽  
pp. 5157-5162 ◽  
Author(s):  
Weixin Su ◽  
Veerendra Kumar ◽  
Yichen Ding ◽  
Rya Ero ◽  
Aida Serra ◽  
...  
Keyword(s):  
Antibiotic Resistance ◽  
Conformational Changes ◽  
Atp Binding ◽  
Peptidyl Transferase ◽  
Exit Site ◽  
Peptidyl Transferase Center ◽  
Biochemical Assays ◽  
Exit Tunnel ◽  
Insight Into ◽  
Atp Binding Cassette

The ribosome is one of the richest targets for antibiotics. Unfortunately, antibiotic resistance is an urgent issue in clinical practice. Several ATP-binding cassette family proteins confer resistance to ribosome-targeting antibiotics through a yet unknown mechanism. Among them, MsrE has been implicated in macrolide resistance. Here, we report the cryo-EM structure of ATP form MsrE bound to the ribosome. Unlike previously characterized ribosomal protection proteins, MsrE is shown to bind to ribosomal exit site. Our structure reveals that the domain linker forms a unique needle-like arrangement with two crossed helices connected by an extended loop projecting into the peptidyl-transferase center and the nascent peptide exit tunnel, where numerous antibiotics bind. In combination with biochemical assays, our structure provides insight into how MsrE binding leads to conformational changes, which results in the release of the drug. This mechanism appears to be universal for the ABC-F type ribosome protection proteins.

scholarly journals Simulation of the Coupling between Nucleotide Binding and Transmembrane Domains in the ATP Binding Cassette Transporter BtuCD

2007 ◽  
Vol 92 (8) ◽  
pp. 2727-2734 ◽  
Author(s):  
Jacob Sonne ◽  
Christian Kandt ◽  
Günther H. Peters ◽  
Flemming Y. Hansen ◽  
Morten Ø. Jensen ◽  
...  
Keyword(s):  
Nucleotide Binding ◽  
Transmembrane Domains ◽  
Atp Binding ◽  
Atp Binding Cassette Transporter ◽  
Atp Binding Cassette

scholarly journals Structural diversity of ABC transporters

2014 ◽  
Vol 143 (4) ◽  
pp. 419-435 ◽  
Author(s):  
Josy ter Beek ◽  
Albert Guskov ◽  
Dirk Jan Slotboom
Keyword(s):  
Abc Transporters ◽  
Transport Mechanism ◽  
Protein Complexes ◽  
Structural Characteristics ◽  
Structural Diversity ◽  
Atp Binding ◽  
Vast Array ◽  
Dependent Protein ◽  
Insight Into ◽  
Atp Binding Cassette

ATP-binding cassette (ABC) transporters form a large superfamily of ATP-dependent protein complexes that mediate transport of a vast array of substrates across membranes. The 14 currently available structures of ABC transporters have greatly advanced insight into the transport mechanism and revealed a tremendous structural diversity. Whereas the domains that hydrolyze ATP are structurally related in all ABC transporters, the membrane-embedded domains, where the substrates are translocated, adopt four different unrelated folds. Here, we review the structural characteristics of ABC transporters and discuss the implications of this structural diversity for mechanistic diversity.

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