Neuroscience in Denmark


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General information

Name (center, department, group or other)
Kastrup Research Group, Biostructural Research Section, DDP, UCPH
Contact name
Jette Sandholm Kastrup
Contact email
jsk#at#sund#dot#ku#dot#dk
Contact title
Professor (MSO)
Date
8. February 2016


Brief description of research activities

> Studies of molecular function and basis for drug design
The goal is to obtain detailed understanding of ligand-gated ion channel receptor structure and function, which is essential for providing a rational basis for design of therapeutic strategies for treating diseases and disorders within the central nervous system. The focus is on studies of full-length solubilized receptors and domains thereof.

> The research group
The research group investigates structure, flexibility, activation mechanisms and binding modes of novel agonists, antagonists and allosteric modulators using various techniques, including protein expression in E. coli and insect cells, X-ray crystallography, isothermal titration calorimetry, circular dichroism and computational chemistry, including computer-aided design and virtual screening.

Keywords

CNS receptors, ionotropic glutamate receptors, structural biology, protein expression and purification, biophysical characterization, X-ray crystallography, analysis of protein-ligand and protein-protein interactions, structure-based drug design

Research tools and techniques

Protein expression in mg amounts
Protein purification in mg amounts
Biophysical characterization, e.g. isothermal titration calorimetry
X-ray macromolecular crystallography
Neutron macromolecular crystallography

Scientific Personnel

No of Associate Professors/Postdocs: 4
No of PhD students: 2
Other: 4

Key references from within the last 5 years

Kristensen AS, Hansen KB, Naur P, Olsen L, Kurtkaya NL, Dravid SM, Kvist T, Yi F, Pøhlsgaard J, Clausen RP, Gajhede M, Kastrup JS, Traynelis SF. Pharmacology
and Structural Analysis of Ligand Binding to the Orthosteric Site of Glutamate-Like GluD2 Receptors. Mol Pharmacol. 2016 Feb;89(2):253-62. doi: 10.1124/mol.115.100909. Epub 2015 Dec 10. PubMed PMID: 26661043.

Christiansen GB, Harbak B, Hede SE, Gouliaev AH, Olsen L, Frydenvang K, Egebjerg J, Kastrup JS, Holm MM. A novel dualistic profile of an allosteric AMPA receptor modulator identified through studies on recombinant receptors, mouse hippocampal synapses and crystal structures. Neuroscience. 2015 Dec 3;310:709-22. doi: 10.1016/j.neuroscience.2015.09.073. Epub 2015 Oct 9. PubMed PMID: 26450748.

Olsen JA, Ahring PK, Kastrup JS, Gajhede M, Balle T. Structural and functional studies of the modulator NS9283 reveal agonist-like mechanism of
action at α4β2 nicotinic acetylcholine receptors. J Biol Chem. 2014 Sep 5;289(36):24911-21. doi: 10.1074/jbc.M114.568097. Epub 2014 Jun 30. PubMed PMID:
24982426; PubMed Central PMCID: PMC4155659.

Olsen JA, Balle T, Gajhede M, Ahring PK, Kastrup JS. Molecular recognition of the neurotransmitter acetylcholine by an acetylcholine binding protein reveals
determinants of binding to nicotinic acetylcholine receptors. PLoS One. 2014 Mar 17;9(3):e91232. doi: 10.1371/journal.pone.0091232. eCollection 2014. PubMed PMID: 24637639; PubMed Central PMCID: PMC3956608.

Nørholm AB, Francotte P, Olsen L, Krintel C, Frydenvang K, Goffin E, Challal S, Danober L, Botez-Pop I, Lestage P, Pirotte B, Kastrup JS. Synthesis,
pharmacological and structural characterization, and thermodynamic aspects of GluA2-positive allosteric modulators with a 3,4-dihydro-2H-1,2,4-benzothiadiazine
1,1-dioxide scaffold. J Med Chem. 2013 Nov 14;56(21):8736-45. doi: 10.1021/jm4012092. Epub 2013 Nov 5. PubMed PMID: 24131202.

Kvist T, Steffensen TB, Greenwood JR, Mehrzad Tabrizi F, Hansen KB, Gajhede M, Pickering DS, Traynelis SF, Kastrup JS, Bräuner-Osborne H. Crystal structure
and pharmacological characterization of a novel N-methyl-D-aspartate (NMDA) receptor antagonist at the GluN1 glycine binding site. J Biol Chem. 2013 Nov
15;288(46):33124-35. doi: 10.1074/jbc.M113.480210. Epub 2013 Sep 26. PubMed PMID: 24072709; PubMed Central PMCID: PMC3829161.

Juknaitė L, Sugamata Y, Tokiwa K, Ishikawa Y, Takamizawa S, Eng A, Sakai R, Pickering DS, Frydenvang K, Swanson GT, Kastrup JS, Oikawa M. Studies on an
(S)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) receptor antagonist IKM-159: asymmetric synthesis, neuroactivity, and structural
characterization. J Med Chem. 2013 Mar 28;56(6):2283-93. doi: 10.1021/jm301590z. Epub 2013 Mar 13. PubMed PMID: 23432124; PubMed Central PMCID: PMC4485398.

Bach A, Clausen BH, Møller M, Vestergaard B, Chi CN, Round A, Sørensen PL, Nissen KB, Kastrup JS, Gajhede M, Jemth P, Kristensen AS, Lundström P, Lambertsen
KL, Strømgaard K. A high-affinity, dimeric inhibitor of PSD-95 bivalently interacts with PDZ1-2 and protects against ischemic brain damage. Proc Natl Acad
Sci U S A. 2012 Feb 28;109(9):3317-22. doi: 10.1073/pnas.1113761109. Epub 2012 Feb 17. PubMed PMID: 22343531; PubMed Central PMCID: PMC3295328.

Venskutonytė R, Frydenvang K, Gajhede M, Bunch L, Pickering DS, Kastrup JS. Binding site and interlobe interactions of the ionotropic glutamate receptor
GluK3 ligand binding domain revealed by high resolution crystal structure in complex with (S)-glutamate. J Struct Biol. 2011 Dec;176(3):307-14. doi:
10.1016/j.jsb.2011.08.014. Epub 2011 Sep 1. Erratum in: J Struct Biol. 2013 Nov;184(2):381. PubMed PMID: 21907808.

Pøhlsgaard J, Frydenvang K, Madsen U, Kastrup JS. Lessons from more than 80 structures of the GluA2 ligand-binding domain in complex with agonists,
antagonists and allosteric modulators. Neuropharmacology. 2011 Jan;60(1):135-50. doi: 10.1016/j.neuropharm.2010.08.004. Epub 2010 Aug 14. Review. PubMed PMID: 20713069.
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