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J. Biol. Chem., Vol. 282, Issue 35, 25726-25736, August 31, 2007

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Partial Agonism and Antagonism of the Ionotropic Glutamate Receptor iGLuR5

STRUCTURES OF THE LIGAND-BINDING CORE IN COMPLEX WITH DOMOIC ACID AND 2-AMINO-3-[5-tert-BUTYL-3-(PHOSPHONOMETHOXY)-4-ISOXAZOLYL]PROPIONIC ACID^*

Helle Hald¹, Peter Naur¹, Darryl S. Pickering^¶, Desiree Sprogøe, Ulf Madsen, Daniel B. Timmermann, Philip K. Ahring, Tommy Liljefors, Arne Schousboe^¶, Jan Egebjerg^||, Michael Gajhede, and Jette Sandholm Kastrup²

From the Departments of Medicinal Chemistry and ^¶Pharmacology and Pharmacotherapy, Faculty of Pharmaceutical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100, Copenhagen, the NeuroSearch A/S, Pederstrupvej 93, DK-2750 Ballerup, and the ^||H. Lundbeck A/S, Ottiliavej 9, DK-2500 Valby, Denmark

More than 50 structures have been reported on the ligand-binding core of the ionotropic glutamate receptor iGluR2 that belongs to the 2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid-type of receptors. In contrast, the ligand-binding core of the kainic acid-type receptor iGluR5 has only been crystallized with three different ligands. Hence, additional structures of iGluR5 are needed to broaden the understanding of the ligand-binding properties of iGluR5, and the conformational changes leading to channel opening and closing. Here, we present two structures of the ligand-binding core of iGluR5; one as a complex with the partial agonist (2S,3S,4S)-3-carboxymethyl-4-[(1Z,3E,5R)-5-carboxy-1-methyl-hexa-1,3-dienyl]-pyrrolidine-2-carboxylic acid (domoic acid) and one as a complex with the antagonist (S)-2-amino-3-[5-tert-butyl-3-(phosphonomethoxy)-4-isoxazolyl]propionic acid ((S)-ATPO). In agreement with the partial agonist activity of domoic acid, the ligand-binding core of the iGluR5 complex is stabilized by domoic acid in a conformation that is 11° more open than the conformation observed in the full agonist (S)-glutamic acid complex. This is primarily caused by the 5-carboxy-1-methyl-hexa-1,3-dienyl moiety of domoic acid and residues Val⁶⁸⁵-Thr⁶⁹⁰ of iGluR5. An even larger domain opening of 28° is introduced upon binding of the antagonist (S)-ATPO. It appears that the span of domain opening is much larger in the ligand-binding core of iGluR5 (30°) compared with what has been observed in iGluR2 (19°). Similarly, much larger variation in the distances between transmembrane linker residues in the two protomers comprising the dimer is observed in iGluR5 as compared with iGluR2.

Received for publication, January 5, 2007 , and in revised form, April 19, 2007.

The atomic coordinates and structure factors (codes 2PBW and 1VSO) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* The work was supported by grants from The Dansync Center for Synchrotron Radiation, The Drug Research Academy, The Ministry of Science, Technology, and Innovation, The Danish Medical Research Council, and The European Community-Access to Research Infrastructure Action of the Improving Human Potential Programme. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed. Tel.: 45-35-33-64-86; Fax: 45-35-33-60-40; E-mail: jsk{at}farma.ku.dk.

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