ArticleThe Biochemical journal2019
ATP-dependent thermostabilization of human P-glycoprotein (ABCB1) is blocked by modulators.
Article in The Biochemical journal, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 51 citations in OpenAlex.
- (N)-Methanocarba Adenosine Derivatives as Dual Modulators of P-Glycoprotein and ABCG2 Transporters.Journal of medicinal chemistry · 2026Article
- Protein Kinase A and assembly of an ABCC4 protein network.Nature communications · 2025Article
- Article
- 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
- Magnolol derivatives as specific and noncytotoxic inhibitors of breast cancer resistance protein (BCRP/ABCG2).Bioorganic chemistry · 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
- Characterization of Potent ABCG2 Inhibitor Derived from Chromone: From the Mechanism of Inhibition to Human Extracellular Vesicles for Drug Delivery.Pharmaceutics · 2023Article
- The Impact of P-Glycoprotein on Opioid Analgesics: What's the Real Meaning in Pain Management and Palliative Care?International journal of molecular sciences · 2022Review
- Graphene oxide (GO)-based nanosheets with combined chemo/photothermal/photodynamic therapy to overcome gastric cancer (GC) paclitaxel resistance by reducing mitochondria-derived adenosine-triphosphate (ATP).Journal of nanobiotechnology · 2021Article
- 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
- Mechanistic basis of breast cancer resistance protein inhibition by new indeno[1,2-b]indoles.Scientific reports · 2021Article
- Cetuximab-Modified Human Serum Albumin Nanoparticles Co-Loaded with Doxorubicin and MDR1 siRNA for the Treatment of Drug-Resistant Breast Tumors.International journal of nanomedicine · 2021Article
- Article
- Disruption of small molecule transporter systems by Transporter-Interfering Chemicals (TICs).FEBS letters · 2020Review
- 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
- Cancer Stem Cells as a Potential Target to Overcome Multidrug Resistance.Frontiers in oncology · 2020Review
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
P-glycoprotein (P-gp), an ATP-binding cassette transporter associated with multidrug resistance in cancer cells, is capable of effluxing a number of xenobiotics as well as anticancer drugs. The transport of molecules through the transmembrane (TM) region of P-gp involves orchestrated conformational changes between inward-open and inward-closed forms, the details of which are still being worked out. Here, we assessed how the binding of transport substrates or modulators in the TM region and the binding of ATP to the nucleotide-binding domains (NBDs) affect the thermostability of P-gp in a membrane environment. P-gp stability after exposure at high temperatures (37-80°C) was assessed by measuring ATPase activity and loss of monomeric P-gp. Our results show that P-gp is significantly thermostabilized (>22°C higher IT50) by the binding of ATP under non-hydrolyzing conditions (in the absence of Mg2+). By using an ATP-binding-deficient mutant (Y401A) and a hydrolysis-deficient mutant (E556Q/E1201Q), we show that thermostabilization of P-gp requires binding of ATP to both NBDs and their dimerization. Additionally, we found that transport substrates do not affect the thermal stability of P-gp either in the absence or presence of ATP; in contrast, inhibitors of P-gp including tariquidar and zosuquidar prevent ATP-dependent thermostabilization in a concentration-dependent manner, by stabilizing the inward-open conformation. Altogether, our data suggest that modulators, which bind in the TM regions, inhibit ATP hydrolysis and drug transport by preventing the ATP-dependent dimerization of the NBDs of P-gp.
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