RESUMEN
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.
Asunto(s)
Proteínas Adaptadoras del Transporte Vesicular/antagonistas & inhibidores , Proteínas Adaptadoras del Transporte Vesicular/química , Cumarinas/química , Leucina/análogos & derivados , Bibliotecas de Moléculas Pequeñas/química , Proteínas Adaptadoras del Transporte Vesicular/genética , Sitios de Unión , Cristalización , Cristalografía por Rayos X , Células HEK293 , Humanos , Leucina/química , Ligandos , Neurotensina/química , Fenilalanina/química , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Relación Estructura-ActividadRESUMEN
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.