ArticleThe Journal of biological chemistry2012
Dynamic ligand-induced conformational rearrangements in P-glycoprotein as probed by fluorescence resonance energy transfer spectroscopy.
Article in The Journal of biological chemistry, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 48 papers.
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Who cites it
48 citing papers in PubMed, 91 citations in OpenAlex.
- The transport activity of the multidrug ABC transporter BmrA does not require a wide separation of the nucleotide-binding domains.The Journal of biological chemistry · 2024Article
- Modeling Substrate Entry into the P-Glycoprotein Efflux Pump at the Blood-Brain Barrier.Journal of medicinal chemistry · 2023Article
- Drug-Induced Conformational Dynamics of P-Glycoprotein Underlies the Transport of Camptothecin Analogs.International journal of molecular sciences · 2023Article
- Advantages and potential limitations of applying AFM kymograph analysis to pharmaceutically relevant membrane proteins in lipid bilayers.Scientific reports · 2023Article
- The human proton pump inhibitors inhibitProceedings of the National Academy of Sciences of the United States of America · 2023Article
- Single-Molecule FRET of Membrane Transport Proteins.Chembiochem : a European journal of chemical biology · 2021Review
- Article
- Human ABCB1 with an ABCB11-like degenerate nucleotide binding site maintains transport activity by avoiding nucleotide occlusion.PLoS genetics · 2020Article
- Article
- The effects of anthracycline drugs on the conformational distribution of mouse P-glycoprotein explains their transport rate differences.Biochemical pharmacology · 2020Article
- Dynamics of ABC Transporter P-glycoprotein in Three Conformational States.Scientific reports · 2019Article
- Site-Directed Fluorescence Approaches for Dynamic Structural Biology of Membrane Peptides and Proteins.Frontiers in molecular biosciences · 2019Review
- Conformational dynamics of the ABC transporter McjD seen by single-molecule FRET.The EMBO journal · 2018Article
- Development of Novel Intramolecular FRET-Based ABC Transporter Biosensors to Identify New Substrates and Modulators.Pharmaceutics · 2018Article
- Single-molecule probing of the conformational homogeneity of the ABC transporter BtuCD.Nature chemical biology · 2018Article
- A Conformationally Gated Model of Methadone and Loperamide Transport by P-Glycoprotein.Journal of pharmaceutical sciences · 2018Article
- Conformational dynamics of P-glycoprotein in lipid nanodiscs and detergent micelles reveal complex motions on a wide time scale.The Journal of biological chemistry · 2018Article
- Dissecting the Forces that Dominate Dimerization of the Nucleotide Binding Domains of ABCB1.Biophysical journal · 2018Article
- The reliability of molecular dynamics simulations of the multidrug transporter P-glycoprotein in a membrane environment.PloS one · 2018Article
- Substrate-induced conformational changes in the nucleotide-binding domains of lipid bilayer-associated P-glycoprotein during ATP hydrolysis.The Journal of biological chemistry · 2017Article
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Authors and funding
4 authors at 2 institutions in 2 countries.
Funding
Abstract
P-glycoprotein (Pgp), a member of the ATP-binding cassette transporter family, functions as an ATP hydrolysis-driven efflux pump to rid the cell of toxic organic compounds, including a variety of drugs used in anticancer chemotherapy. Here, we used fluorescence resonance energy transfer (FRET) spectroscopy to delineate the structural rearrangements the two nucleotide binding domains (NBDs) are undergoing during the catalytic cycle. Pairs of cysteines were introduced into equivalent regions in the N- and C-terminal NBDs for labeling with fluorescent dyes for ensemble and single-molecule FRET spectroscopy. In the ensemble FRET, a decrease of the donor to acceptor (D/A) ratio was observed upon addition of drug and ATP. Vanadate trapping further decreased the D/A ratio, indicating close association of the two NBDs. One of the cysteine mutants was further analyzed using confocal single-molecule FRET spectroscopy. Single Pgp molecules showed fast fluctuations of the FRET efficiencies, indicating movements of the NBDs on a time scale of 10-100 ms. Populations of low, medium, and high FRET efficiencies were observed during drug-stimulated MgATP hydrolysis, suggesting the presence of at least three major conformations of the NBDs during catalysis. Under conditions of vanadate trapping, most molecules displayed high FRET efficiency states, whereas with cyclosporin, more molecules showed low FRET efficiency. Different dwell times of the FRET states were found for the distinct biochemical conditions, with the fastest movements during active turnover. The FRET spectroscopy observations are discussed in context of a model of the catalytic mechanism of Pgp.
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