Acta Crystallographica Section D

Biological Crystallography

Volume 70, Part 2 (February 2014)

research papers

Acta Cryst. (2014). D70, 451-460    [ doi:10.1107/S1399004713030149 ]

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

J. L. Andersen, T. J. Schrøder, S. Christensen, D. Strandbygård, L. T. Pallesen, M. M. García-Alai, S. Lindberg, M. Langgård, J. C. Eskildsen, L. David, L. Tagmose, K. B. Simonsen, P. J. Maltas, L. C. B. Rønn, I. E. M. de Jong, I. J. Malik, J. Egebjerg, J.-J. Karlsson, S. Uppalanchi, D. R. Sakumudi, P. Eradi, S. P. Watson and S. Thirup

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 [pi]-stacking with a phenylalanine.

PDB reference: 4msl

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

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