ArticleThe Journal of biological chemistry2013
Insight into pleiotropic drug resistance ATP-binding cassette pump drug transport through mutagenesis of Cdr1p transmembrane domains.
Article in The Journal of biological chemistry, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 50 citations in OpenAlex.
- Article
- Cdr1 in focus: a personal reflection on multidrug transporter research.FEMS yeast research · 2025Article
- Functional analysis of Candida albicans Cdr1 through homologous and heterologous expression studies.FEMS yeast research · 2025Review
- Use of gain-of-function suppressor screening to elucidateFrontiers in microbiology · 2025Article
- Cryo-EM structures of Candida albicans Cdr1 reveal azole-substrate recognition and inhibitor blocking mechanisms.Nature communications · 2024Article
- Inhibitor-Resistant Mutants Give Important Insights into Candida albicans ABC Transporter Cdr1 Substrate Specificity and Help Elucidate Efflux Pump Inhibition.Antimicrobial agents and chemotherapy · 2022Article
- The Antibiofilm Role of Biotics Family in Vaginal Fungal Infections.Frontiers in microbiology · 2022Review
- Article
- Directed Mutational Strategies Reveal Drug Binding and Transport by the MDR Transporters ofJournal of fungi (Basel, Switzerland) · 2021Review
- FK506 Resistance ofAntimicrobial agents and chemotherapy · 2019Article
- A Xenobiotic Detoxification Pathway through Transcriptional Regulation in Filamentous Fungi.mBio · 2018Article
- Azole resistance in aThe Journal of biological chemistry · 2018Article
- Newly identified motifs in Candida albicans Cdr1 protein nucleotide binding domains are pleiotropic drug resistance subfamily-specific and functionally asymmetric.Scientific reports · 2016Article
- Mutations of charged amino acids at the cytoplasmic end of transmembrane helix 2 affect transport activity of the budding yeast multidrug resistance protein Pdr5p.FEMS yeast research · 2016Article
- A New Endogenous Overexpression System of Multidrug Transporters of Candida albicans Suitable for Structural and Functional Studies.Frontiers in microbiology · 2016Article
- The ABCs of Candida albicans Multidrug Transporter Cdr1.Eukaryotic cell · 2015Review
- Mutational Analysis of Intracellular Loops Identify Cross Talk with Nucleotide Binding Domains of Yeast ABC Transporter Cdr1p.Scientific reports · 2015Article
- Charged/Polar-residue scanning of the hydrophobic face of transmembrane domain 9 of the yeast glutathione transporter, hgt1p, reveals a conformationally critical region for substrate transport.G3 (Bethesda, Md.) · 2015Article
- Milbemycin A4 oxime as a probe of azole transport in Candida glabrata.FEMS yeast research · 2014Article
- Efflux pump proteins in antifungal resistance.Frontiers in pharmacology · 2014Review
Corrections and comments
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Authors and funding
12 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The fungal ATP-binding cassette (ABC) transporter Cdr1 protein (Cdr1p), responsible for clinically significant drug resistance, is composed of two transmembrane domains (TMDs) and two nucleotide binding domains (NBDs). We have probed the nature of the drug binding pocket by performing systematic mutagenesis of the primary sequences of the 12 transmembrane segments (TMSs) found in the TMDs. All mutated proteins were expressed equally well and localized properly at the plasma membrane in the heterologous host Saccharomyces cerevisiae, but some variants differed significantly in efflux activity, substrate specificity, and coupled ATPase activity. Replacement of the majority of the amino acid residues with alanine or glycine yielded neutral mutations, but about 42% of the variants lost resistance to drug efflux substrates completely or selectively. A predicted three-dimensional homology model shows that all the TMSs, apart from TMS4 and TMS10, interact directly with the drug-binding cavity in both the open and closed Cdr1p conformations. However, TMS4 and TMS10 mutations can also induce total or selective drug susceptibility. Functional data and homology modeling assisted identification of critical amino acids within a drug-binding cavity that, upon mutation, abolished resistance to all drugs tested singly or in combinations. The open and closed Cdr1p models enabled the identification of amino acid residues that bordered a drug-binding cavity dominated by hydrophobic residues. The disposition of TMD residues with differential effects on drug binding and transport are consistent with a large polyspecific drug binding pocket in this yeast multidrug transporter.
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