ArticleThe Journal of biological chemistry2013
Gentamicin binds to the megalin receptor as a competitive inhibitor using the common ligand binding motif of complement type repeats: insight from the nmr structure of the 10th complement type repeat domain alone and in complex with gentamicin.
Article in The Journal of biological chemistry, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers.
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38 citing papers in PubMed, 68 citations in OpenAlex.
- Repeated aminoglycoside exposure activates interferon-stimulated genes in human renal proximal tubular models.Archives of toxicology · 2026Article
- Megalin: from structure to function.Nature reviews. Nephrology · 2026Review
- Receptor-mediated endocytosis by Megalin: Exploring its role in ligand interaction and disease mechanisms.Genes & diseases · 2026Review
- Targeting the powerhouse: the mitochondrial perspective on gentamicin-induced kidney injury.Archives of toxicology · 2026Review
- Article
- Windows of susceptibility to neonatal acute kidney injury and nephron loss in a rabbit model.Scientific reports · 2025Article
- The landscape of renal protein S-acylation in mice with lipid-induced nephrotoxicity.Scientific reports · 2025Article
- Protamine protects against vancomycin-induced kidney injury.Antimicrobial agents and chemotherapy · 2025Article
- Elucidating Antibiotic Permeation through theJournal of chemical information and modeling · 2024Article
- Pharmacological Approaches to Hearing Loss.Pharmacological reviews · 2024Review
- Effect of mitochondrial coenzyme-Q10 precursor solanesol in gentamicin-induced experimental nephrotoxicity: Evidence from restoration of ETC-complexes and histopathological alterations.Pharmacology research & perspectives · 2024Article
- Cryo-EM structures elucidate the multiligand receptor nature of megalin.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Article
- Low nephron endowment increases susceptibility to renal stress and chronic kidney disease.JCI insight · 2023Article
- Ataluren suppresses a premature termination codon in an MPS I-H mouse.Journal of molecular medicine (Berlin, Germany) · 2022Article
- Identifying targets to prevent aminoglycoside ototoxicity.Molecular and cellular neurosciences · 2022Review
- In vivo real-time imaging reveals megalin as the aminoglycoside gentamicin transporter into cochlea whose inhibition is otoprotective.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Interference with megalin expression/endocytic function by montelukast mitigates gentamicin nephrotoxicity: Downregulation of ClC-5 expression.Saudi pharmaceutical journal : SPJ : the official publication of the Saudi Pharmaceutical Society · 2022Article
- Mapping Adverse Outcome Pathways for Kidney Injury as a Basis for the Development of Mechanism-Based Animal-Sparing Approaches to Assessment of Nephrotoxicity.Frontiers in toxicology · 2022Article
- Chronic cerebral lipocalin 2 exposure elicits hippocampal neuronal dysfunction and cognitive impairment.Brain, behavior, and immunity · 2021Article
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Authors and funding
5 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Gentamicin is an aminoglycoside widely used in treatments of, in particular, enterococcal, mycobacterial, and severe Gram-negative bacterial infections. Large doses of gentamicin cause nephrotoxicity and ototoxicity, entering the cell via the receptor megalin. Until now, no structural information has been available to describe the interaction with gentamicin in atomic detail, and neither have any three-dimensional structures of domains from the human megalin receptor been solved. To address this gap in our knowledge, we have solved the NMR structure of the 10th complement type repeat of human megalin and investigated its interaction with gentamicin. Using NMR titration data in HADDOCK, we have generated a three-dimensional model describing the complex between megalin and gentamicin. Gentamicin binds to megalin with low affinity and exploits the common ligand binding motif previously described (Jensen, G. A., Andersen, O. M., Bonvin, A. M., Bjerrum-Bohr, I., Etzerodt, M., Thogersen, H. C., O'Shea, C., Poulsen, F. M., and Kragelund, B. B. (2006) J. Mol. Biol. 362, 700-716) utilizing the indole side chain of Trp-1126 and the negatively charged residues Asp-1129, Asp-1131, and Asp-1133. Binding to megalin is highly similar to gentamicin binding to calreticulin. We discuss the impact of this novel insight for the future structure-based design of gentamicin antagonists.
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