Home » Key Drug Discovery Articles » Gentamicin binds to the megalin receptor as a competitive inhibitor using the common ligand binding motif of complement type repeats

Gentamicin binds to the megalin receptor as a competitive inhibitor using the common ligand binding motif of complement type repeats

Gentamicin binds to the megalin receptor as a competitive inhibitor using common ligand binding motif of complement type repeats

Journal Reference

Dagil R, O’Shea C, Nykjær A, Bonvin AM, Kragelund BB.

J Biol Chem. 2013 Feb 8;288(6):4424-35.

Structural Biology and NMR Laboratory, Department of Biology, University of Copenhagen, Ole Maaloes Vej 5, DK-2200 Copenhagen, Denmark.

 

Abstract

 

Background:

Gentamicin (GNT) is an aminoglycoside widely used in treatments of, in particular, enterococcal, mycobacterial, and severe Gram negative bacterial infections. It causes nephrotoxicity and ototoxicity using megalin as a key cellular uptake site, but no structural data are available. Large doses of gentamicin cause nephrotoxicity and ototoxicity, entering the cell via the receptor megalin.

 

Results:

We have solved the NMR structure of the 10th complement type repeat of human megalin and investigated its interaction with GNT. Using NMR titration data in HADDOCK, we have generated a three-dimensional model describing the complex between megalin and gentamicin. It binds to megalin with low affinity and exploits the common ligand binding motif.

Conclusion:

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. This first structure of human megalin in complex with GNT suggests electrostatics to be the main binding determinant. Structure-based design of gentamicin antagonists may now be possible.

Go To PubMed