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

The identification of the first small-molecule ligand of the neuronal receptor sortilin and structure determination of the receptor–ligand complex are reported. 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.
Authors:
 [1] ; ;  [2] ;  [1] ;  [3] ;  [1] ; ; ; ; ; ; ; ; ; ; ; ;  [2] ; ; more »;  [4] ;  [2] ;  [1] « less
  1. Aarhus University, Gustav Wieds Vej 10C, 8000 Aarhus C (Denmark)
  2. H. Lundbeck A/S, Ottiliavej 9, 2500 Valby (Denmark)
  3. Aarhus University, Ole Worms Allé 3, 8000 Aarhus C (Denmark)
  4. GVK BioScience, Plot No. 28 A, IDA Nacharam, Hyderabad 500 076 (India)
Publication Date:
OSTI Identifier:
22347814
Resource Type:
Journal Article
Resource Relation:
Journal Name: Acta Crystallographica. Section D: Biological Crystallography; Journal Volume: 70; Journal Issue: Pt 2; Other Information: PMCID: PMC3940197; PMID: 24531479; PUBLISHER-ID: dw5079; OAI: oai:pubmedcentral.nih.gov:3940197; Copyright (c) Andersen et al. 2014; This is an open-access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original authors and source are cited.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
Denmark
Language:
English
Subject:
75 CONDENSED MATTER PHYSICS, SUPERCONDUCTIVITY AND SUPERFLUIDITY; CRYSTALLIZATION; CRYSTALS; LAYERS; LIGANDS; MEMBRANES; MOLECULES; RECEPTORS; RESOLUTION