ArticleeLife2024
Tracing the substrate translocation mechanism in P-glycoprotein.
Article in eLife, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed.
- Functional implications of the conformational landscape of a multidrug transporter revealed by Zebrafish Abcb4 structures.Nature communications · 2026Article
- A dual sensor regulates P-glycoprotein's structural plasticity.bioRxiv : the preprint server for biology · 2026Article
- Drug-bound outward-facing conformation of a heterodimeric ABC exporter suggests a putative mechanism of drug translocation.Nature communications · 2025Article
- Modeling protein conformational ensembles by guiding AlphaFold2 with Double Electron Electron Resonance (DEER) distance distributions.Nature communications · 2025Article
- P-glycoprotein modulates the fluidity gradient of the plasma membrane of multidrug resistant CHO cells.FEBS letters · 2025Article
- Predictive and Prognostic Relevance of ABC Transporters for Resistance to Anthracycline Derivatives.Biomolecules · 2025Article
- A robust and interpretable graph neural network-based protocol for predicting p-glycoprotein substrates.Briefings in bioinformatics · 2025Article
- Cryo-EM Structures of Apo and DDT-Bound P-Glycoprotein in Yellowfin Tuna.Environmental science & technology · 2025Article
- Mapping the Role of P-gp in Multidrug Resistance: Insights from Recent Structural Studies.International journal of molecular sciences · 2025Review
- Revisiting the Role of the Leucine Plug/Valve in the Human ABCG2 Multidrug Transporter.International journal of molecular sciences · 2025Article
- Advancing Molecular Simulations: Merging Physical Models, Experiments, and AI to Tackle Multiscale Complexity.The journal of physical chemistry letters · 2025Review
- Cryo-EM of human P-glycoprotein reveals an intermediate occluded conformation during active drug transport.Nature communications · 2025Article
- Rhodamine6G and Hœchst33342 narrow BmrA conformational spectrum for a more efficient use of ATP.Nature communications · 2025Article
- Nucleotide asymmetry and flexible linker dynamics modulate drug efflux cycle of P-glycoprotein, A computational study.Computational and structural biotechnology journal · 2025Article
- Modeling Conformational Transitions of Biomolecules from Atomic Force Microscopy Images using Normal Mode Analysis.The journal of physical chemistry. B · 2024Article
- 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
- Coupling the role of lipids to the conformational dynamics of the ABC transporter P-glycoprotein.Biophysical journal · 2024Article
- The transport activity of the multidrug ABC transporter BmrA does not require a wide separation of the nucleotide-binding domains.The Journal of biological chemistry · 2024Article
Corrections and comments
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Authors and funding
13 authors.
Funding
Abstract
P-glycoprotein (Pgp) is a prototypical ATP-binding cassette (ABC) transporter of great biological and clinical significance.Pgp confers cancer multidrug resistance and mediates the bioavailability and pharmacokinetics of many drugs (Juliano and Ling, 1976; Ueda et al., 1986; Sharom, 2011). Decades of structural and biochemical studies have provided insights into how Pgp binds diverse compounds (Loo and Clarke, 2000; Loo et al., 2009; Aller et al., 2009; Alam et al., 2019; Nosol et al., 2020; Chufan et al., 2015), but how they are translocated through the membrane has remained elusive. Here, we covalently attached a cyclic substrate to discrete sites of Pgp and determined multiple complex structures in inward- and outward-facing states by cryoEM. In conjunction with molecular dynamics simulations, our structures trace the substrate passage across the membrane and identify conformational changes in transmembrane helix 1 (TM1) as regulators of substrate transport. In mid-transport conformations, TM1 breaks at glycine 72. Mutation of this residue significantly impairs drug transport of Pgp in vivo, corroborating the importance of its regulatory role. Importantly, our data suggest that the cyclic substrate can exit Pgp without the requirement of a wide-open outward-facing conformation, diverting from the common efflux model for Pgp and other ABC exporters. The substrate transport mechanism of Pgp revealed here pinpoints critical targets for future drug discovery studies of this medically relevant system.
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