ABSTRACT
Sortilin is a type I membrane glycoprotein belonging to the vacuolar protein sorting 10 protein (Vps10p) family of sorting receptors and is most abundantly expressed in the central nervous system. Sortilin has emerged as a key player in the regulation of neuronal viability and has been implicated as a possible therapeutic target in a range of disorders. Here, the identification of AF40431, the first reported small-molecule ligand of sortilin, is reported. Crystals of the sortilin-AF40431 complex were obtained by co-crystallization and the structure of the complex was solved to 2.7â Å resolution. AF40431 is bound in the neurotensin-binding site of sortilin, with the leucine moiety of AF40431 mimicking the binding mode of the C-terminal leucine of neurotensin and the 4-methylumbelliferone moiety of AF40431 forming π-stacking with a phenylalanine.
Subject(s)
Adaptor Proteins, Vesicular Transport/antagonists & inhibitors , Adaptor Proteins, Vesicular Transport/chemistry , Coumarins/chemistry , Leucine/analogs & derivatives , Small Molecule Libraries/chemistry , Adaptor Proteins, Vesicular Transport/genetics , Binding Sites , Crystallization , Crystallography, X-Ray , HEK293 Cells , Humans , Leucine/chemistry , Ligands , Neurotensin/chemistry , Phenylalanine/chemistry , Recombinant Proteins/chemistry , Recombinant Proteins/genetics , Structure-Activity RelationshipABSTRACT
The identification of the novel, selective, orally bioavailable Sortilin inhibitor AF38469 is described. Structure-activity relationships and syntheses are reported, along with an X-ray crystal structure of the sortilin-AF38469 protein-inhibitor complex.
