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

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

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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