ArticleNature communications2025
Cryo-EM of human P-glycoprotein reveals an intermediate occluded conformation during active drug transport.
Article in Nature communications, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed.
- The Antidepressant Drug Clomipramine Inhibits the ABC Transporter BmrA.Chembiochem : a European journal of chemical biology · 2026Article
- Functional implications of the conformational landscape of a multidrug transporter revealed by Zebrafish Abcb4 structures.Nature communications · 2026Article
- Structural and mechanistic insights into the inhibition of Plasmodium falciparum MDR1.Nature communications · 2026Article
- A dual sensor regulates P-glycoprotein's structural plasticity.bioRxiv : the preprint server for biology · 2026Article
- An Investigation of the Conformational Dynamics of ABC Exporter PCAT1 using Microsecond-Level MD Simulations.bioRxiv : the preprint server for biology · 2026Article
- Predictive modelling of the COMATOSE transporter reveals a conserved ligand binding pocket for acyl-CoAs.Scientific reports · 2026Article
- N-Alkylated Monoterpene Indole Alkaloid Derivatives as Chemotherapy Adjuvants That Overcome P-glycoprotein-Mediated Multidrug Resistance in Cancer Cells, Spheroids and Patient-Derived Colorectal Cancer Organoids.Drug design, development and therapy · 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
- Glucosamine activates intestinal P-glycoprotein inhibiting drug absorption.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
- Pharmacological effects, molecular mechanisms and strategies to improve bioavailability of curcumin in the treatment of neurodegenerative diseases.Frontiers in pharmacology · 2025Review
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Authors and funding
2 authors.
Funding
Abstract
P-glycoprotein (Pgp) is an important human multidrug transporter that contributes to pharmacokinetics and multidrug resistance. Despite decades of study, the conformation transition cycle of Pgp undergoing active drug transport is not defined, thus the precise relevance of all available Pgp structures to uninterrupted multidrug transport remains unclear. Here, we use cryo-EM of membrane-embedded human Pgp under continuous turnover conditions to analyze the conformational ensembles of Pgp transporting distinct substrates. These results delineate multiple conformations including inward-facing and closed conformations, highlighting the occluded conformation as a critical intermediate state between transporter closure and substrate release. A combination of structural, functional, and computational studies reveals the transmembrane helices 4 and 10 undergoing drastic rearrangement to coordinate substrate binding, occlusion, and release, and identifies a peripheral site involved in substrate capture and Pgp inhibition. Together, our results provide a set of snapshots of Pgp undergoing continuous drug transport, unveiling the intricate interplay between transporter dynamics and drug movement, and shed light on the mechanism of polyspecificity.
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