Identification of the first small-molecule ligand of the neuronal receptor sortilin and structure determination of the receptor-ligand complex.

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 2.7?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 ?-stacking with a phenylalanine.

SUBMITTER: Andersen JL 

PROVIDER: S-EPMC3940197 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature