ArticleThe Journal of biological chemistry2017
Substrate-induced conformational changes in the nucleotide-binding domains of lipid bilayer-associated P-glycoprotein during ATP hydrolysis.
Article in The Journal of biological chemistry, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
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Who cites it
34 citing papers in PubMed, 70 citations in OpenAlex.
- A dual sensor regulates P-glycoprotein's structural plasticity.bioRxiv : the preprint server for biology · 2026Article
- Conformational equilibrium of an ABC transporter analyzed by luminescence resonance energy transfer.Biophysical journal · 2025Article
- Article
- 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
- Drug-Induced Conformational Dynamics of P-Glycoprotein Underlies the Transport of Camptothecin Analogs.International journal of molecular sciences · 2023Article
- Genetics ofCancers · 2023Review
- Advantages and potential limitations of applying AFM kymograph analysis to pharmaceutically relevant membrane proteins in lipid bilayers.Scientific reports · 2023Article
- Lipid environment determines the drug-stimulated ATPase activity of P-glycoprotein.Frontiers in molecular biosciences · 2023Article
- ATP Mimetic Attack on the Nucleotide-Binding Domain to Overcome ABC Transporter Mediated Chemoresistance.ACS medicinal chemistry letters · 2022Article
- Structural and functional investigation of ABC transporter STE6-2p fromProceedings of the National Academy of Sciences of the United States of America · 2022Article
- Involvement of Multidrug Resistance Modulators in the Regulation of the Mitochondrial Permeability Transition Pore.Membranes · 2022Article
- Long Range Communication between the Drug-Binding Sites and Nucleotide Binding Domains of the Efflux Transporter ABCB1.Biochemistry · 2022Article
- Article
- Peptide Tags and Domains for Expression and Detection of Mammalian Membrane Proteins at the Cell Surface.Methods in molecular biology (Clifton, N.J.) · 2022Article
- Active participation of membrane lipids in inhibition of multidrug transporter P-glycoprotein.Chemical science · 2021Article
- Conformational changes in the nucleotide-binding domains of P-glycoprotein induced by ATP hydrolysis.FEBS letters · 2021Article
- Enzymatic trans-bilayer lipid transport: Mechanisms, efficiencies, slippage, and membrane curvature.Biochimica et biophysica acta. Biomembranes · 2021Review
- Does the ATP-bound EQ mutant reflect the pre- or post-ATP hydrolysis state in the catalytic cycle of human P-glycoprotein (ABCB1)?FEBS letters · 2021Article
- Article
- Production of a human mitochondrial ABC transporter in E. coli.Protein expression and purification · 2021Article
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Authors and funding
7 authors at 3 institutions in 3 countries.
Funding
Abstract
P-glycoprotein (Pgp) is an efflux pump important in multidrug resistance of cancer cells and in determining drug pharmacokinetics. Pgp is a prototype ATP-binding cassette transporter with two nucleotide-binding domains (NBDs) that bind and hydrolyze ATP. Conformational changes at the NBDs (the Pgp engines) lead to changes across Pgp transmembrane domains that result in substrate translocation. According to current alternating access models (substrate-binding pocket accessible only to one side of the membrane at a time), binding of ATP promotes NBD dimerization, resulting in external accessibility of the drug-binding site (outward-facing, closed NBD conformation), and ATP hydrolysis leads to dissociation of the NBDs with the subsequent return of the accessibility of the binding site to the cytoplasmic side (inward-facing, open NBD conformation). However, previous work has not investigated these events under near-physiological conditions in a lipid bilayer and in the presence of transport substrate. Here, we used luminescence resonance energy transfer (LRET) to measure the distances between the two Pgp NBDs. Pgp was labeled with LRET probes, reconstituted in lipid nanodiscs, and the distance between the NBDs was measured at 37 °C. In the presence of verapamil, a substrate that activates ATP hydrolysis, the NBDs of Pgp reconstituted in nanodiscs were never far apart during the hydrolysis cycle, and we never observed the NBD-NBD distances of tens of Å that have previously been reported. However, we found two main conformations that coexist in a dynamic equilibrium under all conditions studied. Our observations highlight the importance of performing studies of efflux pumps under near-physiological conditions, in a lipid bilayer, at 37 °C, and during substrate-stimulated hydrolysis.
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