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P-glycoprotein (Pgp, ABCB1) is an ATP-Binding Cassette (ABC) transporter that is associated with the development of multidrug resistance in cancer cells. Pgp transports a variety of chemically dissimilar amphipathic compounds using the energy from ATP hydrolysis. In the present study, to elucidate the binding sites on Pgp for substrates and modulators, we employed site-directed mutagenesis, cell- and membrane-based assays, molecular modeling and docking. We generated single, double and triple mutants with substitutions of the Y307, F343, Q725, F728, F978 and V982 residues at the proposed drug-binding site with cys in a cysless Pgp, and expressed them in insect and mammalian cells using a baculovirus expression system. All the mutant proteins were expressed at the cell surface to the same extent as the cysless wild-type Pgp. With substitution of three residues of the pocket (Y307, Q725 and V982) with cysteine in a cysless Pgp, QZ59S-SSS, cyclosporine A, tariquidar, valinomycin and FSBA lose the ability to inhibit the labeling of Pgp with a transport substrate, [(125)I]-Iodoarylazidoprazosin, indicating these drugs cannot bind at their primary binding sites. However, the drugs can modulate the ATP hydrolysis of the mutant Pgps, demonstrating that they bind at secondary sites. In addition, the transport of six fluorescent substrates in HeLa cells expressing triple mutant (Y307C/Q725C/V982C) Pgp is also not significantly altered, showing that substrates bound at secondary sites are still transported. The homology modeling of human Pgp and substrate and modulator docking studies support the biochemical and transport data. In aggregate, our results demonstrate that a large flexible pocket in the Pgp transmembrane domains is able to bind chemically diverse compounds. When residues of the primary drug-binding site are mutated, substrates and modulators bind to secondary sites on the transporter and more than one transport-active binding site is available for each substrate.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3857843 | PMC |
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0082463 | PLOS |
Front Immunol
December 2024
Laboratory of Molecular Medicine, Department of Clinical Immunology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
Throughout the COVID-19 pandemic, the emergence of new viral variants has challenged public health efforts, often evading antibody responses generated by infections and vaccinations. This immune escape has led to waves of breakthrough infections, raising questions about the efficacy and durability of immune protection. Here we focus on the impact of SARS-CoV-2 Delta and Omicron spike mutations on ACE-2 receptor binding, protein stability, and immune response evasion.
View Article and Find Full Text PDFMol Clin Oncol
February 2025
First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China.
Breast cancer (BC) is a malignant tumor, that damages the physical health of female patients. It is crucial to develop new treatment strategies for BC, as this disease significantly affects the quality of life of women in both developing and developed countries, despite the existence of effective treatment options to reduce mortality. Recently, several researchers have been studying circular RNAs (circRNAs) in BC due to their stability and sponge function.
View Article and Find Full Text PDF3 Biotech
January 2025
Department of Zoology, College of Science, King Saud University, 11451 Riyadh, Saudi Arabia.
The present study evaluated the antioxidant and anti-inflammatory properties of (CA) fruit extract against bisphenol A (BPA)-induced ovarian injury in female Wistar rats. The antioxidant activity was estimated by the total antioxidant capacity (TAC) and superoxide radical (NBT) content. For the in vivo analyses, 24 animals were divided into the following 4 groups: the control group; the BPA group (50 mg/kg BW BPA for 30 days); the BPA + CA group (50 mg/kg BW BPA and 50 mg/kg BW CA); and the CA group (50 mg/kg BW CA).
View Article and Find Full Text PDFFront Plant Sci
December 2024
National Key Laboratory for Tropical Crop Breeding, School of Breeding and Multiplication (Sanya Institute of Breeding and Multiplication)/College of Tropical Agriculture and Forestry, Hainan University, Sanya, Hainan, China.
Introduction: () is a small transcription factor family known for its role in various developmental processes in plants, particularly in binding GA motifs and regulating flower and seed development. However, research on the functional characteristics and target genes of in coconut () is limited.
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J Med Chem
December 2024
Univ. Bordeaux, CNRS, Bordeaux INP, CBMN, UMR 5248, IECB, F-33607 Pessac, France.
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