ArticleProceedings of the National Academy of Sciences of the United States of America2020
Reversing the direction of drug transport mediated by the human multidrug transporter P-glycoprotein.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
26 citing papers in PubMed, 44 citations in OpenAlex.
- Real-time photoactivated SRS imaging enables spatiotemporally controlled nitroxyl release and therapeutic guidance in vivo.Nature communications · 2026Article
- Self-assembled verteporfin nanoparticles decrease drug efflux by P-glycoprotein without light activation in drug-resistant cancer cells.Bioengineering & translational medicine · 2026Article
- Integrated machine learning and molecular dynamics framework for predicting and elucidating ABCB1 allocrite interactions.Briefings in bioinformatics · 2026Article
- The Evolution of ABC Importers.Journal of molecular biology · 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
- The mycobacterial ABC transporter IrtAB employs a membrane-facing crevice for siderophore-mediated iron uptake.Nature communications · 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
- Bidirectional ATP-driven transport of cobalamin by the mycobacterial ABC transporter BacA.Nature communications · 2024Article
- Article
- Structural View of Cryo-Electron Microscopy-Determined ATP-Binding Cassette Transporters in Human Multidrug Resistance.Biomolecules · 2024Review
- Deciphering the functional role of clinical mutations in ABCB1, ABCC1, and ABCG2 ABC transporters in endometrial cancer.Frontiers in pharmacology · 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
- 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
- Advances in the structure, mechanism and targeting of chemoresistance-linked ABC transporters.Nature reviews. Cancer · 2023Review
- Residues from Homologous Transmembrane Helices 4 and 10 Are Critical for P-Glycoprotein (ABCB1)-Mediated Drug Transport.Cancers · 2023Article
- Deep mutational scan of a drug efflux pump reveals its structure-function landscape.Nature chemical biology · 2023Article
- Maternal and Fetal Exposure to (-)-ΔDrug metabolism and disposition: the biological fate of chemicals · 2023Article
- Systemic RNA Interference Defective (SID) genes modulate dopaminergic neurodegeneration in C. elegans.PLoS genetics · 2022Article
- Strategies and Mechanism in Reversing Intestinal Drug Efflux in Oral Drug Delivery.Pharmaceutics · 2022Review
- Extended-ensemble docking to probe dynamic variation of ligand binding sites during large-scale structural changes of proteins.Chemical science · 2022Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
8 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
P-glycoprotein (P-gp), also known as ABCB1, is a cell membrane transporter that mediates the efflux of chemically dissimilar amphipathic drugs and confers resistance to chemotherapy in most cancers. Homologous transmembrane helices (TMHs) 6 and 12 of human P-gp connect the transmembrane domains with its nucleotide-binding domains, and several residues in these TMHs contribute to the drug-binding pocket. To investigate the role of these helices in the transport function of P-gp, we substituted a group of 14 conserved residues (seven in both TMHs 6 and 12) with alanine and generated a mutant termed 14A. Although the 14A mutant lost the ability to pump most of the substrates tested out of cancer cells, surprisingly, it acquired a new function. It was able to import four substrates, including rhodamine 123 (Rh123) and the taxol derivative flutax-1. Similar to the efflux function of wild-type P-gp, we found that uptake by the 14A mutant is ATP hydrolysis-, substrate concentration-, and time-dependent. Consistent with the uptake function, the mutant P-gp also hypersensitizes HeLa cells to Rh123 by 2- to 2.5-fold. Further mutagenesis identified residues from both TMHs 6 and 12 that synergistically form a switch in the central region of the two helices that governs whether a given substrate is pumped out of or into the cell. Transforming P-gp or an ABC drug exporter from an efflux transporter into a drug uptake pump would constitute a paradigm shift in efforts to overcome cancer drug resistance.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.