ArticleFASEB journal : official publication of the Federation of American Societies for Experimental Biology2020
ABCG2 requires a single aromatic amino acid to "clamp" substrates and inhibitors into the binding pocket.
Article in FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 40 citations in OpenAlex.
- Article
- Protein Kinase A and assembly of an ABCC4 protein network.Nature communications · 2025Article
- Folic Acid Ameliorates Neuronal Ferroptosis in Aging by Up-Regulating SLC7A11-GSH-GPXInternational journal of molecular sciences · 2025Article
- ABCG2 Transporter: From Structure to Function-Current Insights and Open Questions.International journal of molecular sciences · 2025Review
- Article
- A Structural Bioinformatics-Guided Study of Adenosine Triphosphate-Binding Cassette (ABC) Transporters and Their Substrates.Membranes · 2025Article
- Tumor-acquired somatic mutation affects conformation to abolish ABCG2-mediated drug resistance.Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy · 2024Article
- How Cryo-EM Has Expanded Our Understanding of Membrane Transporters.Drug metabolism and disposition: the biological fate of chemicals · 2023Review
- Restriction of access to the central cavity is a major contributor to substrate selectivity in plant ABCG transporters.Cellular and molecular life sciences : CMLS · 2023Article
- The More the Better-Investigation of PolymethoxylatedPharmaceutics · 2023Article
- Differential dynamics and direct interaction of bound ligands with lipids in multidrug transporter ABCG2.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Structural and molecular characterization of lopinavir and ivermectin as breast cancer resistance protein (BCRP/ABCG2) inhibitors.EXCLI journal · 2023Article
- Interaction of crown ethers with the ABCG2 transporter and their implication for multidrug resistance reversal.Histochemistry and cell biology · 2022Article
- Development and Validation of a Sensitive and Specific LC-MS/MS Method for IWR-1-Endo, a Wnt Signaling Inhibitor: Application to a Cerebral Microdialysis Study.Molecules (Basel, Switzerland) · 2022Article
- Inhibition of ABCG2 transporter by lapatinib enhances 5-aminolevulinic acid-mediated protoporphyrin IX fluorescence and photodynamic therapy response in human glioma cell lines.Biochemical pharmacology · 2022Article
- ABCG2/BCRP transport mechanism revealed through kinetically excited targeted molecular dynamics simulations.Computational and structural biotechnology journal · 2022Article
- Small molecule kinase inhibitors enhance aminolevulinic acid-mediated protoporphyrin IX fluorescence and PDT response in triple negative breast cancer cell lines.Journal of biomedical optics · 2021Article
- Structures of ABCG2 under turnover conditions reveal a key step in the drug transport mechanism.Nature communications · 2021Article
- Multidrug Resistance in Mammals and Fungi-From MDR to PDR: A Rocky Road from Atomic Structures to Transport Mechanisms.International journal of molecular sciences · 2021Review
- Analysis of Sequence Divergence in Mammalian ABCGs Predicts a Structural Network of Residues That Underlies Functional Divergence.International journal of molecular sciences · 2021Article
Corrections and comments
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Authors and funding
13 authors at 3 institutions in 3 countries.
Funding
Abstract
ATP-binding cassette sub-family G member 2 (ABCG2) is a homodimeric ATP-binding cassette (ABC) transporter that not only has a key role in helping cancer cells to evade the cytotoxic effects of chemotherapy, but also in protecting organisms from multiple xeno- and endobiotics. Structural studies indicate that substrate and inhibitor (ligands) binding to ABCG2 can be differentiated quantitatively by the number of amino acid contacts, with inhibitors displaying more contacts. Although binding is the obligate initial step in the transport cycle, there is no empirical evidence for one amino acid being primarily responsible for ligand binding. By mutagenesis and biochemical studies, we demonstrated that the phylogenetically conserved amino acid residue, F439, was critical for both transport and the binding of multiple substrates and inhibitors. Structural modeling implied that the π-π interactions from each F439 monomer mediated the binding of a surprisingly diverse array of structurally unrelated substrates and inhibitors and that this symmetrical π-π interaction "clamps" the ligand into the binding pocket. Key molecular features of diverse ABCG2 ligands using the π-π clamp along with structural studies created a pharmacophore model. These novel findings have important therapeutic implications because key properties of ligands interacting with ABCG2 have been disovered. Furthermore, mechanistic insights have been revealed by demonstrating that for ABCG2 a single amino acid is essential for engaging and initiating transport of multiple drugs and xenobiotics.
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