title: Identification of the first small-molecule ligand of the neuronal receptor sortilin and structure determination of the receptor-ligand complex.
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.
authors: The Lundbeck Foundation Research Centre MIND, Department of Molecular Biology and Genetics, Aarhus University, Gustav Wieds Vej 10C, 8000 Aarhus C, Denmark.
authors: Jacob Lauwring
authors: JL
authors: Andersen
authors: Neuroscience Drug Discovery, H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark.
authors: Tenna Juul
authors: TJ
authors: Schrøder
authors: Neuroscience Drug Discovery, H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark.
authors: Søren
authors: S
authors: Christensen
authors: The Lundbeck Foundation Research Centre MIND, Department of Molecular Biology and Genetics, Aarhus University, Gustav Wieds Vej 10C, 8000 Aarhus C, Denmark.
authors: Dorthe
authors: D
authors: Strandbygård
authors: The Lundbeck Foundation Research Centre MIND, Department of Biomedicine, Aarhus University, Ole Worms Allé 3, 8000 Aarhus C, Denmark.
authors: Lone Tjener
authors: LT
authors: Pallesen
authors: The Lundbeck Foundation Research Centre MIND, Department of Molecular Biology and Genetics, Aarhus University, Gustav Wieds Vej 10C, 8000 Aarhus C, Denmark.
authors: Maria Marta
authors: MM
authors: García-Alai
authors: Neuroscience Drug Discovery, H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark.
authors: Samsa
authors: S
authors: Lindberg
authors: Neuroscience Drug Discovery, H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark.
authors: Morten
authors: M
authors: Langgård
authors: Neuroscience Drug Discovery, H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark.
authors: Jørgen Calí
authors: JC
authors: Eskildsen
authors: Neuroscience Drug Discovery, H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark.
authors: Laurent
authors: L
authors: David
authors: Neuroscience Drug Discovery, H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark.
authors: Lena
authors: L
authors: Tagmose
authors: Neuroscience Drug Discovery, H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark.
authors: Klaus Baek
authors: KB
authors: Simonsen
authors: Neuroscience Drug Discovery, H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark.
authors: Philip James
authors: PJ
authors: Maltas
authors: Neuroscience Drug Discovery, H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark.
authors: Lars Christian Biilmann
authors: LC
authors: Rønn
authors: Neuroscience Drug Discovery, H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark.
authors: Inge E M
authors: IE
authors: de Jong
authors: Neuroscience Drug Discovery, H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark.
authors: Ibrahim John
authors: IJ
authors: Malik
authors: Neuroscience Drug Discovery, H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark.
authors: Jan
authors: J
authors: Egebjerg
authors: Neuroscience Drug Discovery, H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark.
authors: Jens-Jacob
authors: JJ
authors: Karlsson
authors: Medicinal Chemistry, GVK BioScience, Plot No. 28 A, IDA Nacharam, Hyderabad 500 076, India.
authors: Srinivas
authors: S
authors: Uppalanchi
authors: Medicinal Chemistry, GVK BioScience, Plot No. 28 A, IDA Nacharam, Hyderabad 500 076, India.
authors: Durga Rao
authors: DR
authors: Sakumudi
authors: Medicinal Chemistry, GVK BioScience, Plot No. 28 A, IDA Nacharam, Hyderabad 500 076, India.
authors: Pradheep
authors: P
authors: Eradi
authors: Neuroscience Drug Discovery, H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark.
authors: Steven P
authors: SP
authors: Watson
authors: The Lundbeck Foundation Research Centre MIND, Department of Molecular Biology and Genetics, Aarhus University, Gustav Wieds Vej 10C, 8000 Aarhus C, Denmark.
authors: Søren
authors: S
authors: Thirup
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000235:genetics; D001665:Binding Sites; D003374:Coumarins / Q000737:chemistry*; D003460:Crystallization; D018360:Crystallography, X-Ray; D057809:HEK293 Cells; D006801:Humans; D007930:Leucine / Q000031:analogs & derivatives* / Q000737:chemistry; D008024:Ligands; D009496:Neurotensin / Q000737:chemistry; D010649:Phenylalanine / Q000737:chemistry; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics; D054852:Small Molecule Libraries / Q000737:chemistry*; D013329:Structure-Activity Relationship; D000099183:Sortilin
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D003374:Coumarins; D007930:Leucine; D008024:Ligands; D009496:Neurotensin; D010649:Phenylalanine; D011994:Recombinant Proteins; D054852:Small Molecule Libraries; D000099183:Sortilin; C000592441:AF40431
keywords: AF40431; Alzheimer's disease; Vps10p; ligands; proNGF; small molecules; sortilin