ArticleThe Journal of biological chemistry2015
Mapping the Binding Site of the Inhibitor Tariquidar That Stabilizes the First Transmembrane Domain of P-glycoprotein.
Article in The Journal of biological chemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 43 citations in OpenAlex.
- Inward opening (IO) to outward opening (OO) 'catalytic transition' and OO to IO 'relaxation' of P-glycoprotein: to investigate the role of helices in efflux through targeted molecular dynamics simulation.In silico pharmacology · 2025Article
- Mutational analysis reveals the importance of residues of the access tunnel inhibitor site to human P-glycoprotein (ABCB1)-mediated transport.Protein science : a publication of the Protein Society · 2024Article
- Coupling the role of lipids to the conformational dynamics of the ABC transporter P-glycoprotein.Biophysical journal · 2024Article
- Structural insight into binding site access and ligand recognition by human ABCB1.bioRxiv : the preprint server for biology · 2024Article
- Second-site suppressor mutations reveal connection between the drug-binding pocket and nucleotide-binding domain 1 of human P-glycoprotein (ABCB1).Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy · 2023Article
- Ligand's Partition to the Lipid Bilayer Should Be Accounted for When Estimating Their Affinity to Proteins.Molecules (Basel, Switzerland) · 2023Article
- Interaction of a Homologous Series of Amphiphiles with P-glycoprotein in a Membrane Environment-Contributions of Polar and Non-Polar Interactions.Pharmaceutics · 2023Article
- ATP Mimetic Attack on the Nucleotide-Binding Domain to Overcome ABC Transporter Mediated Chemoresistance.ACS medicinal chemistry letters · 2022Article
- Article
- Active participation of membrane lipids in inhibition of multidrug transporter P-glycoprotein.Chemical science · 2021Article
- Lysine 268 adjacent to transmembrane helix 5 of hamster P-glycoprotein is the major photobinding site of iodomycin in CHO B30 cells.FEBS open bio · 2021Article
- Computational Insights into Allosteric Conformational Modulation of P-Glycoprotein by Substrate and Inhibitor Binding.Molecules (Basel, Switzerland) · 2020Article
- Mamma Mia, P-glycoprotein binds again.FEBS letters · 2020Review
- Article
- Replacing the eleven native tryptophans by directed evolution produces an active P-glycoprotein with site-specific, non-conservative substitutions.Scientific reports · 2020Article
- ATP-dependent thermostabilization of human P-glycoprotein (ABCB1) is blocked by modulators.The Biochemical journal · 2019Article
- Newly Synthesized Oxygenated Xanthones as Potential P-Glycoprotein Activators:Molecules (Basel, Switzerland) · 2019Article
- Tenulin and isotenulin inhibit P-glycoprotein function and overcome multidrug resistance in cancer cells.Phytomedicine : international journal of phytotherapy and phytopharmacology · 2019Article
- Glesatinib, a c-MET/SMO Dual Inhibitor, Antagonizes P-glycoprotein Mediated Multidrug Resistance in Cancer Cells.Frontiers in oncology · 2019Article
- Structure of a zosuquidar and UIC2-bound human-mouse chimeric ABCB1.Proceedings of the National Academy of Sciences of the United States of America · 2018Article
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
ABC (ATP-binding cassette) transporters are clinically important because drug pumps like P-glycoprotein (P-gp, ABCB1) confer multidrug resistance and mutant ABC proteins are responsible for many protein-folding diseases such as cystic fibrosis. Identification of the tariquidar-binding site has been the subject of intensive molecular modeling studies because it is the most potent inhibitor and corrector of P-gp. Tariquidar is a unique P-gp inhibitor because it locks the pump in a conformation that blocks drug efflux but activates ATPase activity. In silico docking studies have identified several potential tariquidar-binding sites. Here, we show through cross-linking studies that tariquidar most likely binds to sites within the transmembrane (TM) segments located in one wing or at the interface between the two wings (12 TM segments form 2 divergent wings). We then introduced arginine residues at all positions in the 12 TM segments (223 mutants) of P-gp. The rationale was that a charged residue in the drug-binding pocket would disrupt hydrophobic interaction with tariquidar and inhibit its ability to rescue processing mutants or stimulate ATPase activity. Arginines introduced at 30 positions significantly inhibited tariquidar rescue of a processing mutant and activation of ATPase activity. The results suggest that tariquidar binds to a site within the drug-binding pocket at the interface between the TM segments of both structural wings. Tariquidar differed from other drug substrates, however, as it stabilized the first TM domain. Stabilization of the first TM domain appears to be a key mechanism for high efficiency rescue of ABC processing mutants that cause disease.
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