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.