ArticleProceedings of the National Academy of Sciences of the United States of America2020
Cryo-EM structures reveal distinct mechanisms of inhibition of the human multidrug transporter ABCB1.
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 134 papers, 1 of them a synthesis that pooled it.
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Who cites it
134 citing papers in PubMed, 1 synthesis or guideline pooled it, 241 citations in OpenAlex.
- Protein Spatial Structure Meets Artificial Intelligence: Revolutionizing Drug Synergy-Antagonism in Precision Medicine.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Pooled it
- Discovery of novel coumarin-containing triazolo[1,5-a]pyrimidine derivatives as potent ABCB1 inhibitor for modulation of multidrug resistance.Journal of enzyme inhibition and medicinal chemistry · 2026Article
- Rational design of pyrazole-oxime hybrids as dual-targeting agents for glioma and breast cancer brain metastasis.Naunyn-Schmiedeberg's archives of pharmacology · 2026Article
- The nematode Caenorhabditis elegans has a cationic amphiphilic drug (CAD) defense system.PLoS biology · 2026Article
- FromACS omega · 2026Article
- Effects of Amino Acid Point Mutations on the Local Hydrophobicity, Structural Stability, and Conformational Flexibility of P-Glycoprotein.Biomolecules · 2026Article
- Review
- Functional implications of the conformational landscape of a multidrug transporter revealed by Zebrafish Abcb4 structures.Nature communications · 2026Article
- Synthesis of Novel Acetylene-Containing Phosphonates, Their Antiviral Activity, and Their Cytotoxicity to Different Cancer Cell Lines.Molecules (Basel, Switzerland) · 2026Article
- Structural and mechanistic insights into the inhibition of Plasmodium falciparum MDR1.Nature communications · 2026Article
- First GC/MS Profiling and Cytotoxic Evaluation of Physalis acutifolia (Solanaceae) Essential Oils: Insights From Molecular Docking and ADME Predictions.Chemistry & biodiversity · 2026Article
- Mapping the inhibition landscape of P-glycoprotein via conformational ensemble docking.Scientific reports · 2026Article
- Thioxanthone-Mediated Cytoprotection Against Cisplatin Toxicity: Exploring the Potential Involvement of P-Glycoprotein Through Computational and Experimental Approaches.Journal of xenobiotics · 2026Article
- A dual sensor regulates P-glycoprotein's structural plasticity.bioRxiv : the preprint server for biology · 2026Article
- Integrated machine learning and molecular dynamics framework for predicting and elucidating ABCB1 allocrite interactions.Briefings in bioinformatics · 2026Article
- (N)-Methanocarba Adenosine Derivatives as Dual Modulators of P-Glycoprotein and ABCG2 Transporters.Journal of medicinal chemistry · 2026Article
- Cloning, structural and functional characterization of the ABCB1 transporter of the Eurasian bullfinch (Frontiers in veterinary science · 2026Article
- Visualizing the Functional Dynamics of P-Glycoprotein and Its Modulation by Elacridar via High-Speed Atomic Force Microscopy.International journal of molecular sciences · 2025Article
- Article
- H89 Reverses Multidrug Resistance in Colorectal Cancer by Inhibiting the ATPase Activity of ABCB1.Biomedicines · 2025Article
74 more citing papers are in PubMed but not listed here.
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Authors and funding
7 authors at 3 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
ABCB1 detoxifies cells by exporting diverse xenobiotic compounds, thereby limiting drug disposition and contributing to multidrug resistance in cancer cells. Multiple small-molecule inhibitors and inhibitory antibodies have been developed for therapeutic applications, but the structural basis of their activity is insufficiently understood. We determined cryo-EM structures of nanodisc-reconstituted, human ABCB1 in complex with the Fab fragment of the inhibitory, monoclonal antibody MRK16 and bound to a substrate (the antitumor drug vincristine) or to the potent inhibitors elacridar, tariquidar, or zosuquidar. We found that inhibitors bound in pairs, with one molecule lodged in the central drug-binding pocket and a second extending into a phenylalanine-rich cavity that we termed the "access tunnel." This finding explains how inhibitors can act as substrates at low concentration, but interfere with the early steps of the peristaltic extrusion mechanism at higher concentration. Our structural data will also help the development of more potent and selective ABCB1 inhibitors.
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