ArticleThe Journal of biological chemistry2018
Conformational dynamics of P-glycoprotein in lipid nanodiscs and detergent micelles reveal complex motions on a wide time scale.
Article in The Journal of biological chemistry, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed.
- Design of Fluorescent Membrane Scaffold Proteins for Nanodiscs.ACS chemical biology · 2026Article
- Probing protein-lipid interactions by hydrogen/deuterium exchange-mass spectrometry: advances, challenges and future directions.Chemical science · 2026Review
- Design of Fluorescent Membrane Scaffold Proteins for Nanodiscs.bioRxiv : the preprint server for biology · 2026Article
- Bidirectional communication between nucleotide and substrate binding sites in a type IV multidrug ABC transporter.Nature communications · 2025Article
- 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
- Advantages and potential limitations of applying AFM kymograph analysis to pharmaceutically relevant membrane proteins in lipid bilayers.Scientific reports · 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
- Hydrogen/deuterium exchange-mass spectrometry of integral membrane proteins in native-like environments: current scenario and the way forward.Essays in biochemistry · 2023Article
- Advances in Hydrogen/Deuterium Exchange Mass Spectrometry and the Pursuit of Challenging Biological Systems.Chemical reviews · 2022Review
- Long Range Communication between the Drug-Binding Sites and Nucleotide Binding Domains of the Efflux Transporter ABCB1.Biochemistry · 2022Article
- Assessing the Role of Lipids in the Molecular Mechanism of Membrane Proteins.International journal of molecular sciences · 2021Review
- Active participation of membrane lipids in inhibition of multidrug transporter P-glycoprotein.Chemical science · 2021Article
- Article
- Conformational maps of human 20S proteasomes reveal PA28- and immuno-dependent inter-ring crosstalks.Nature communications · 2020Article
- A glimpse into the molecular mechanism of integral membrane proteins through hydrogen-deuterium exchange mass spectrometry.Protein science : a publication of the Protein Society · 2020Review
- Bridging protein structure, dynamics, and function using hydrogen/deuterium-exchange mass spectrometry.Protein science : a publication of the Protein Society · 2020Review
- Mechanisms of promiscuity among drug metabolizing enzymes and drug transporters.The FEBS journal · 2020Review
- Dynamics and Location of the Allosteric Midazolam Site in Cytochrome P4503A4 in Lipid Nanodiscs.Biochemistry · 2020Article
- ATP-dependent thermostabilization of human P-glycoprotein (ABCB1) is blocked by modulators.The Biochemical journal · 2019Article
Corrections and comments
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Authors and funding
3 authors.
Funding
Abstract
P-glycoprotein (P-gp) is a highly substrate-promiscuous efflux transporter that plays a critical role in drug disposition. P-gp utilizes ATP hydrolysis by nucleotide-binding domains (NBDs) to drive transitions between inward-facing (IF) conformations that bind drugs and outward-facing (OF) conformations that release them to the extracellular solution. However, the details of the protein dynamics within either macroscopic IF or OF conformation remain uncharacterized, and the functional role of local dynamics has not been determined. In this work we measured the local dynamics of the IF state of P-gp in lipid nanodiscs and in detergent solution by hydrogen-deuterium (H/D) exchange MS. We observed "EX1 exchange kinetics," or bimodal kinetics, for several peptides distributed in both NBDs, particularly for P-gp in the lipid nanodiscs. Remarkably, the EX1 kinetics occurred on several time scales, ranging from seconds to hours, suggesting highly complex, and correlated, motions. The results indicate at least three distinct conformational states in the ligand-free P-gp and suggest a rough conformational landscape. Addition of excess ATP and vanadate, to favor the OF conformations, caused a generalized, but modest, decrease in H/D exchange throughout the NBDs and slowed the EX1 kinetic transitions of several peptides. The functional implications of the results are consistent with the possibility that conformational selection provides a source of substrate promiscuity.
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Registered trials
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