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

Jacob Lauwring Andersen; Tenna Juul Schrøder; Søren Christensen; Dorthe Jepsen Strandbygård; Lone Tjener Pallesen; Maria Marta Garcia Alai; Samsa Lindberg; Morten Langgård; Jørgen Calí Eskildsen; Laurent David; Lena Tagmose; Klaus Baek Simonsen; Philip James Maltas; Lars Christian Biilmann Rønn; Inge Elisabeth Maria de Jong; Ibrahim John Malik; Jan Egebjerg; Jens Jacob Karlsson; Srinivas Uppalanchi; Durga Rao Sakumudi; Pradheep Eradi; Steven P Watson; Søren Thirup

doi:10.1107/S1399004713030149

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

Jacob Lauwring Andersen, Tenna Juul Schrøder, Søren Christensen, Dorthe Jepsen Strandbygård, Lone Tjener Pallesen, Maria Marta Garcia Alai, Samsa Lindberg, Morten Langgård, Jørgen Calí Eskildsen, Laurent David, Lena Tagmose, Klaus Baek Simonsen, Philip James Maltas, Lars Christian Biilmann Rønn, Inge Elisabeth Maria de Jong, Ibrahim John Malik, Jan Egebjerg, Jens Jacob Karlsson, Srinivas Uppalanchi, Durga Rao SakumudiPradheep Eradi, Steven P Watson, Søren Thirup

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

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.

Original language	English
Journal	Acta Crystallographica. Section D: Biological Crystallography
Volume	70
Issue	Part 2
Pages (from-to)	451-460
Number of pages	10
ISSN	0907-4449
DOIs	https://doi.org/10.1107/S1399004713030149
Publication status	Published - Feb 2014

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Andersen, J. L., Schrøder, T. J., Christensen, S., Strandbygård, D. J., Pallesen, L. T., Garcia Alai, M. M., Lindberg, S., Langgård, M., Eskildsen, J. C., David, L., Tagmose, L., Simonsen, K. B., Maltas, P. J., Rønn, L. C. B., de Jong, I. E. M., Malik, I. J., Egebjerg, J., Karlsson, J. J., Uppalanchi, S., ... Thirup, S. (2014). Identification of the first small-molecule ligand of the neuronal receptor sortilin and structure determination of the receptor-ligand complex. Acta Crystallographica. Section D: Biological Crystallography, 70(Part 2), 451-460. https://doi.org/10.1107/S1399004713030149

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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 {\AA} 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.",

author = "Andersen, {Jacob Lauwring} and Schr{\o}der, {Tenna Juul} and S{\o}ren Christensen and Strandbyg{\aa}rd, {Dorthe Jepsen} and Pallesen, {Lone Tjener} and {Garcia Alai}, {Maria Marta} and Samsa Lindberg and Morten Langg{\aa}rd and Eskildsen, {J{\o}rgen Cal{\'i}} and Laurent David and Lena Tagmose and Simonsen, {Klaus Baek} and Maltas, {Philip James} and R{\o}nn, {Lars Christian Biilmann} and {de Jong}, {Inge Elisabeth Maria} and Malik, {Ibrahim John} and Jan Egebjerg and Karlsson, {Jens Jacob} and Srinivas Uppalanchi and Sakumudi, {Durga Rao} and Pradheep Eradi and Watson, {Steven P} and S{\o}ren Thirup",

year = "2014",

month = feb,

doi = "10.1107/S1399004713030149",

language = "English",

volume = "70",

pages = "451--460",

journal = "Acta Crystallographica. Section D: Biological Crystallography",

issn = "0907-4449",

publisher = "International Union of Crystallography",

number = "Part 2",

}

Andersen, JL, Schrøder, TJ, Christensen, S, Strandbygård, DJ , Pallesen, LT, Garcia Alai, MM, Lindberg, S, Langgård, M, Eskildsen, JC, David, L, Tagmose, L, Simonsen, KB, Maltas, PJ, Rønn, LCB, de Jong, IEM, Malik, IJ, Egebjerg, J, Karlsson, JJ, Uppalanchi, S, Sakumudi, DR, Eradi, P, Watson, SP & Thirup, S 2014, 'Identification of the first small-molecule ligand of the neuronal receptor sortilin and structure determination of the receptor-ligand complex', Acta Crystallographica. Section D: Biological Crystallography, vol. 70, no. Part 2, pp. 451-460. https://doi.org/10.1107/S1399004713030149

Identification of the first small-molecule ligand of the neuronal receptor sortilin and structure determination of the receptor-ligand complex. / Andersen, Jacob Lauwring; Schrøder, Tenna Juul; Christensen, Søren et al.
In: Acta Crystallographica. Section D: Biological Crystallography, Vol. 70, No. Part 2, 02.2014, p. 451-460.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

TY - JOUR

T1 - Identification of the first small-molecule ligand of the neuronal receptor sortilin and structure determination of the receptor-ligand complex

AU - Andersen, Jacob Lauwring

AU - Schrøder, Tenna Juul

AU - Christensen, Søren

AU - Strandbygård, Dorthe Jepsen

AU - Pallesen, Lone Tjener

AU - Garcia Alai, Maria Marta

AU - Lindberg, Samsa

AU - Langgård, Morten

AU - Eskildsen, Jørgen Calí

AU - David, Laurent

AU - Tagmose, Lena

AU - Simonsen, Klaus Baek

AU - Maltas, Philip James

AU - Rønn, Lars Christian Biilmann

AU - de Jong, Inge Elisabeth Maria

AU - Malik, Ibrahim John

AU - Egebjerg, Jan

AU - Karlsson, Jens Jacob

AU - Uppalanchi, Srinivas

AU - Sakumudi, Durga Rao

AU - Eradi, Pradheep

AU - Watson, Steven P

AU - Thirup, Søren

PY - 2014/2

Y1 - 2014/2

N2 - 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.

AB - 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.

U2 - 10.1107/S1399004713030149

DO - 10.1107/S1399004713030149

M3 - Journal article

C2 - 24531479

SN - 0907-4449

VL - 70

SP - 451

EP - 460

JO - Acta Crystallographica. Section D: Biological Crystallography

JF - Acta Crystallographica. Section D: Biological Crystallography

IS - Part 2

ER -

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

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