ArticleProceedings of the National Academy of Sciences of the United States of America2013
Mass spectrometry reveals synergistic effects of nucleotides, lipids, and drugs binding to a multidrug resistance efflux pump.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 92 papers.
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Who cites it
92 citing papers in PubMed, 168 citations in OpenAlex.
- Transcriptome and Metabolome Dissection of Multilayered Pydiflumetofen Resistance Mechanisms inInternational journal of molecular sciences · 2026Article
- Probing the Annular Lipid Belt of Membrane Proteins Using Native Mass Spectrometry.Methods in molecular biology (Clifton, N.J.) · 2026Article
- Characterization of two orthologs of bacterial intramembrane metalloprotease RseP by native mass spectrometry.Analytical and bioanalytical chemistry · 2025Article
- Expanding the Reach of Membrane Protein-Ligand Interaction Studies Through the Integration of Mass Spectrometry and Membrane Mimetics.Proteomics · 2025Review
- P-glycoprotein modulates the fluidity gradient of the plasma membrane of multidrug resistant CHO cells.FEBS letters · 2025Article
- Native Mass Spectrometry of Membrane Protein-Lipid Interactions in Different Detergent Environments.Analytical chemistry · 2024Article
- Native mass spectrometry and structural studies reveal modulation of MsbA-nucleotide interactions by lipids.Nature communications · 2024Article
- TREK2 Lipid Binding Preferences Revealed by Native Mass Spectrometry.Journal of the American Society for Mass Spectrometry · 2024Article
- Native mass spectrometry of membrane protein-lipid interactions in different detergent environments.bioRxiv : the preprint server for biology · 2024Article
- Native mass spectrometry analysis of conjugated HSA and BSA complexes with various flavonoids.The Analyst · 2024Article
- Double and triple thermodynamic mutant cycles reveal the basis for specific MsbA-lipid interactions.eLife · 2024Article
- Native mass spectrometry of proteoliposomes containing integral and peripheral membrane proteins.Chemical science · 2023Article
- Metabolome and Transcriptome Combinatory Profiling Reveals Fluconazole Resistance Mechanisms ofMicroorganisms · 2023Article
- Article
- Double and triple thermodynamic mutant cycles reveal the basis for specific MsbA-lipid interactions.bioRxiv : the preprint server for biology · 2023Article
- Combining native mass spectrometry and lipidomics to uncover specific membrane protein-lipid interactions from natural lipid sources.Chemical science · 2023Article
- Cross-Linking Mass Spectrometry on P-Glycoprotein.International journal of molecular sciences · 2023Article
- Structural mass spectrometry approaches to understand multidrug efflux systems.Essays in biochemistry · 2023Review
- Article
- Lipid environment determines the drug-stimulated ATPase activity of P-glycoprotein.Frontiers in molecular biosciences · 2023Article
32 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
12 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Multidrug resistance is a serious barrier to successful treatment of many human diseases, including cancer, wherein chemotherapeutics are exported from target cells by membrane-embedded pumps. The most prevalent of these pumps, the ATP-Binding Cassette transporter P-glycoprotein (P-gp), consists of two homologous halves each comprising one nucleotide-binding domain and six transmembrane helices. The transmembrane region encapsulates a hydrophobic cavity, accessed by portals in the membrane, that binds cytotoxic compounds as well as lipids and peptides. Here we use mass spectrometry (MS) to probe the intact P-gp small molecule-bound complex in a detergent micelle. Activation in the gas phase leads to formation of ions, largely devoid of detergent, yet retaining drug molecules as well as charged or zwitterionic lipids. Measuring the rates of lipid binding and calculating apparent KD values shows that up to six negatively charged diacylglycerides bind more favorably than zwitterionic lipids. Similar experiments confirm binding of cardiolipins and show that prior binding of the immunosuppressant and antifungal antibiotic cyclosporin A enhances subsequent binding of cardiolipin. Ion mobility MS reveals that P-gp exists in an equilibrium between different states, readily interconverted by ligand binding. Overall these MS results show how concerted small molecule binding leads to synergistic effects on binding affinities and conformations of a multidrug efflux pump.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.