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

  • Acta Crystallogr D Biol Crystallogr. 2014 Feb;70(Pt 2):451-60. doi: 10.1107/S1399004713030149.
Jacob Lauwring Andersen  1 ,  Tenna Juul Schrøder  2 ,  Søren Christensen  2 ,  Dorthe Strandbygård  1 ,  Lone Tjener Pallesen  3 ,  Maria Marta García-Alai  1 ,  Samsa Lindberg  2 ,  Morten Langgård  2 ,  Jørgen Calí Eskildsen  2 ,  Laurent David  2 ,  Lena Tagmose  2 ,  Klaus Baek Simonsen  2 ,  Philip James Maltas  2 ,  Lars Christian Biilmann Rønn  2 ,  Inge E M de Jong  2 ,  Ibrahim John Malik  2 ,  Jan Egebjerg  2 ,  Jens-Jacob Karlsson  2 ,  Srinivas Uppalanchi  4 ,  Durga Rao Sakumudi  4 ,  Pradheep Eradi  4 ,  Steven P Watson  2 ,  Søren Thirup  1
Affiliations
  • 1. The Lundbeck Foundation Research Centre MIND, Department of Molecular Biology and Genetics, Aarhus University, Gustav Wieds Vej 10C, 8000 Aarhus C, Denmark.
  • 2. Neuroscience Drug Discovery, H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark.
  • 3. The Lundbeck Foundation Research Centre MIND, Department of Biomedicine, Aarhus University, Ole Worms Allé 3, 8000 Aarhus C, Denmark.
  • 4. Medicinal Chemistry, GVK BioScience, Plot No. 28 A, IDA Nacharam, Hyderabad 500 076, India.
PMID: 24531479 DOI: 10.1107/S1399004713030149
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 π-stacking with a phenylalanine.

Keywords
AF40431; Alzheimer's disease; Vps10p; ligands; proNGF; small molecules; sortilin.
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