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

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 π‐stacking with a phenylalanine.