ArticleBiochemical pharmacology2016
Drug-protein hydrogen bonds govern the inhibition of the ATP hydrolysis of the multidrug transporter P-glycoprotein.
Article in Biochemical pharmacology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 47 papers.
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Who cites it
47 citing papers in PubMed, 87 citations in OpenAlex.
- Ferroptosis as a Novel Therapeutic Strategy to Overcome Multidrug Resistance in Colorectal Cancer.Pharmaceuticals (Basel, Switzerland) · 2026Review
- Umbralisib antagonizes multidrug resistance in ABCB1-overexpressing cancer cells.Frontiers in oncology · 2026Article
- H89 Reverses Multidrug Resistance in Colorectal Cancer by Inhibiting the ATPase Activity of ABCB1.Biomedicines · 2025Article
- Influence of Tariquidar, an ABC Transporter Inhibitor, on the CaPharmaceuticals (Basel, Switzerland) · 2025Article
- P-Glycoprotein as a Therapeutic Target in Hematological Malignancies: A Challenge to Overcome.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
- USP14 increases the sensitivity of retinoblastoma to cisplatin by mediating the ferroptosis.Naunyn-Schmiedeberg's archives of pharmacology · 2024Article
- Structural insight into binding site access and ligand recognition by human ABCB1.bioRxiv : the preprint server for biology · 2024Article
- Formononetin Defeats Multidrug-Resistant Cancers by Induction of Oxidative Stress and Suppression of P-Glycoprotein.International journal of molecular sciences · 2024Article
- A Novel 3-ACS omega · 2023Article
- Study Models of Drug-Drug Interactions Involving P-Glycoprotein: The Potential Benefit of P-Glycoprotein Modulation at the Kidney and Intestinal Levels.Molecules (Basel, Switzerland) · 2023Review
- 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
- Synergistic Inhibitory Effect of Quercetin and Cyanidin-3O-Sophoroside on ABCB1.International journal of molecular sciences · 2023Article
- In Silico and In Vitro Identification of P-Glycoprotein Inhibitors from a Library of 375 Phytochemicals.International journal of molecular sciences · 2023Article
- On-target inhibition of Cryptosporidium parvum by nitazoxanide (NTZ) and paclitaxel (PTX) validated using a novel MDR1-transgenic host cell model and algorithms to quantify the effect on the parasite target.PLoS neglected tropical diseases · 2023Article
- P-glycoprotein (ABCB1) - weak dipolar interactions provide the key to understanding allocrite recognition, binding, and transport.Cancer drug resistance (Alhambra, Calif.) · 2023Review
- Analysis of P-Glycoprotein Transport Cycle Reveals a New Way to Identify Efflux Inhibitors.ACS omega · 2022Article
- Novel Epoxides of Soloxolone Methyl: An Effect of the Formation of Oxirane Ring and Stereoisomerism on Cytotoxic Profile, Anti-Metastatic and Anti-Inflammatory Activities In Vitro and In Vivo.International journal of molecular sciences · 2022Article
- JAK2 Inhibitor, Fedratinib, Inhibits P-gp Activity and Co-Treatment Induces Cytotoxicity in Antimitotic Drug-Treated P-gp Overexpressing Resistant KBV20C Cancer Cells.International journal of molecular sciences · 2022Article
- Long Range Communication between the Drug-Binding Sites and Nucleotide Binding Domains of the Efflux Transporter ABCB1.Biochemistry · 2022Article
Corrections and comments
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
P-glycoprotein (P-gp) is a member of the ATP-binding cassette transporter superfamily. This multidrug transporter utilizes energy from ATP hydrolysis for the efflux of a variety of hydrophobic and amphipathic compounds including anticancer drugs. Most of the substrates and modulators of P-gp stimulate its basal ATPase activity, although some inhibit it. The molecular mechanisms that are in play in either case are unknown. In this report, mutagenesis and molecular modeling studies of P-gp led to the identification of a pair of phenylalanine-tyrosine structural motifs in the transmembrane region that mediate the inhibition of ATP hydrolysis by certain drugs (zosuquidar, elacridar and tariquidar), with high affinity (IC50's ranging from 10 to 30nM). Upon mutation of any of these residues, drugs that inhibit the ATPase activity of P-gp switch to stimulation of the activity. Molecular modeling revealed that the phenylalanine residues F978 and F728 interact with tyrosine residues Y953 and Y310, respectively, in an edge-to-face conformation, which orients the tyrosines in such a way that they establish hydrogen-bond contacts with the inhibitor. Biochemical investigations along with transport studies in intact cells showed that the inhibitors bind at a high affinity site to produce inhibition of ATP hydrolysis and transport function. Upon mutation, they bind at lower affinity sites, stimulating ATP hydrolysis and only poorly inhibiting transport. These results also reveal that screening chemical compounds for their ability to inhibit the basal ATP hydrolysis can be a reliable tool to identify modulators with high affinity for P-gp.
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