ArticleBiochemical pharmacology2017
Global alteration of the drug-binding pocket of human P-glycoprotein (ABCB1) by substitution of fifteen conserved residues reveals a negative correlation between substrate size and transport efficiency.
Article in Biochemical pharmacology, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 37 citations in OpenAlex.
- (N)-Methanocarba Adenosine Derivatives as Dual Modulators of P-Glycoprotein and ABCG2 Transporters.Journal of medicinal chemistry · 2026Article
- Mapping the Role of P-gp in Multidrug Resistance: Insights from Recent Structural Studies.International journal of molecular sciences · 2025Review
- Conversion of Human Multidrug Transporter P-glycoprotein (ABCB1) from Drug Efflux to Uptake Pump: Evidence for a Switch Region Modulating the Direction of Substrate Transport.Journal of molecular biology · 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
- Novel players in the development of chemoresistance in ovarian cancer: ovarian cancer stem cells, non-coding RNA and nuclear receptors.Cancer drug resistance (Alhambra, Calif.) · 2024Review
- Deciphering resistance mechanisms and novel strategies to overcome drug resistance in ovarian cancer: a comprehensive review.Oncology research · 2024Review
- 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
- Residues from Homologous Transmembrane Helices 4 and 10 Are Critical for P-Glycoprotein (ABCB1)-Mediated Drug Transport.Cancers · 2023Article
- The Alternating Access Mechanism in Mammalian Multidrug Resistance Transporters and Their Bacterial Homologs.Membranes · 2023Article
- Interaction of a Homologous Series of Amphiphiles with P-glycoprotein in a Membrane Environment-Contributions of Polar and Non-Polar Interactions.Pharmaceutics · 2023Article
- Interaction of AEuropean journal of medicinal chemistry · 2022Article
- Mechanisms of chemotherapy resistance in ovarian cancer.Cancer drug resistance (Alhambra, Calif.) · 2022Review
- Characterization and tissue localization of zebrafish homologs of the human ABCB1 multidrug transporter.Scientific reports · 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
- Clinically-Relevant ABC Transporter for Anti-Cancer Drug Resistance.Frontiers in pharmacology · 2021Review
- Reversing the direction of drug transport mediated by the human multidrug transporter P-glycoprotein.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- Cryo-EM structures reveal distinct mechanisms of inhibition of the human multidrug transporter ABCB1.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- Replacing the eleven native tryptophans by directed evolution produces an active P-glycoprotein with site-specific, non-conservative substitutions.Scientific reports · 2020Article
- Drug Repositioning for P-Glycoprotein Mediated Co-Expression Networks in Colorectal Cancer.Frontiers in oncology · 2020Article
- ATP-dependent thermostabilization of human P-glycoprotein (ABCB1) is blocked by modulators.The Biochemical journal · 2019Article
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Authors and funding
3 authors at 3 institutions in 1 country.
Funding
Abstract
P-glycoprotein (P-gp), an ATP-dependent efflux pump, is linked to the development of multidrug resistance in cancer cells. However, the drug-binding sites and translocation pathways of this transporter are not yet well-characterized. We recently demonstrated the important role of tyrosine residues in regulating P-gp ATP hydrolysis via hydrogen bond formations with high affinity modulators. Since tyrosine is both a hydrogen bond donor and acceptor, and non-covalent interactions are key in drug transport, in this study we investigated the global effect of enrichment of tyrosine residues in the drug-binding pocket on the drug binding and transport function of P-gp. By employing computational analysis, 15 conserved residues in the drug-binding pocket of human P-gp that interact with substrates were identified and then substituted with tyrosine, including 11 phenylalanine (F72, F303, F314, F336, F732, F759, F770, F938, F942, F983, F994), two leucine (L339, L975), one isoleucine (I306), and one methionine (M949). Characterization of the tyrosine-rich P-gp mutant in HeLa cells demonstrated that this major alteration in the drug-binding pocket by introducing fifteen additional tyrosine residues is well tolerated and has no measurable effect on total or cell surface expression of this mutant. Although the tyrosine-enriched mutant P-gp could transport small to moderate size (<1000 Daltons) fluorescent substrates, its ability to transport large (>1000 Daltons) substrates such as NBD-cyclosporine A, Bodipy-paclitaxel and Bodipy-vinblastine was significantly decreased. This was further supported by the physico-chemical characterization of seventeen tested substrates, which revealed a negative correlation between drug transport and molecular size for the tyrosine-enriched P-gp mutant.
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