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

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  • Jacob Lauwring Andersen, Denmark
  • Tenna Juul Schrøder, Neuroscience Drug Discovery, H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark.
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  • Søren Christensen, Denmark
  • Dorthe Jepsen Strandbygård
  • Lone Tjener Pallesen
  • Maria Marta Garcia Alai
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  • Samsa Lindberg, Neuroscience Drug Discovery, H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark.
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  • Morten Langgård, Neuroscience Drug Discovery, H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark.
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  • Jørgen Calí Eskildsen, Neuroscience Drug Discovery, H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark.
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  • Laurent David, Neuroscience Drug Discovery, H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark.
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  • Lena Tagmose, Neuroscience Drug Discovery, H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark.
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  • Klaus Baek Simonsen, Neuroscience Drug Discovery, H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark.
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  • Philip James Maltas, Neuroscience Drug Discovery, H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark.
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  • Lars Christian Biilmann Rønn, Neuroscience Drug Discovery, H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark.
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  • Inge Elisabeth Maria de Jong, LUKKET: 2012 Institut for Farmakologi og Farmakote, Denmark
  • Ibrahim John Malik, Neuroscience Drug Discovery, H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark.
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  • Jan Egebjerg, Neuroscience Drug Discovery, H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark.
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  • Jens Jacob Karlsson, Neuroscience Drug Discovery, H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark.
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  • Srinivas Uppalanchi, Medicinal Chemistry, GVK BioScience, Plot No. 28 A, IDA Nacharam, Hyderabad 500 076, India.
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  • Durga Rao Sakumudi, Medicinal Chemistry, GVK BioScience, Plot No. 28 A, IDA Nacharam, Hyderabad 500 076, India.
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  • Pradheep Eradi, Medicinal Chemistry, GVK BioScience, Plot No. 28 A, IDA Nacharam, Hyderabad 500 076, India.
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  • Steven P Watson, Neuroscience Drug Discovery, H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark.
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  • Søren Thirup
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.
Original languageEnglish
JournalActa Crystallographica. Section D: Biological Crystallography
Volume70
IssuePart 2
Pages (from-to)451-460
Number of pages10
ISSN0907-4449
DOIs
Publication statusPublished - Feb 2014

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