2m0p
Solution structure of the tenth complement type repeat of human megalin
Structural highlights
DiseaseLRP2_HUMAN Donnai-Barrow syndrome. Donnai-Barrow syndrome (DBS) [MIM:222448: Rare autosomal recessive disorder characterized by major malformations including agenesis of the corpus callosum, congenital diaphragmatic hernia, facial dysmorphology, ocular anomalies, sensorineural hearing loss and developmental delay. The FOAR syndrome was first described as comprising facial anomalies, ocular anomalies, sensorineural hearing loss, and proteinuria. DBS and FOAR were first described as distinct disorders but the classic distinguishing features between the 2 disorders were presence of proteinuria and absence of diaphragmatic hernia and corpus callosum anomalies in FOAR. Early reports noted that the 2 disorders shared many phenotypic features and may be identical. Although there is variability in the expression of some features (e.g., agenesis of the corpus callosum and proteinuria), DBS and FOAR are now considered to represent the same entity. Note=The disease is caused by mutations affecting the gene represented in this entry.[1] FunctionLRP2_HUMAN Acts together with cubilin to mediate HDL endocytosis (By similarity). May participate in regulation of parathyroid-hormone and para-thyroid-hormone-related protein release. Publication Abstract from PubMedis 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 tenth 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 et al. (2006) J Mol Biol 362, 700-716) utilizing the indole side chain of Trp1126 and the negatively charged residues Asp1129, Asp1131 and Asp1133. 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. Gentamicin Binds to Megalin as a Competitive Inhibitor Using the Common Ligand Binding Motif of Complement Type Repeats.,Dagil R, O'Shea C, Nykjaer A, Bonvin AM, Kragelund BB J Biol Chem. 2012 Dec 27. PMID:23275343[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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