1m5c
From Proteopedia
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'''X-RAY STRUCTURE OF THE GLUR2 LIGAND BINDING CORE (S1S2J) IN COMPLEX WITH Br-HIBO AT 1.65 A RESOLUTION''' | '''X-RAY STRUCTURE OF THE GLUR2 LIGAND BINDING CORE (S1S2J) IN COMPLEX WITH Br-HIBO AT 1.65 A RESOLUTION''' | ||
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[[Category: Liljefors, T.]] | [[Category: Liljefors, T.]] | ||
[[Category: Mayer, M L.]] | [[Category: Mayer, M L.]] | ||
| - | [[Category: | + | [[Category: Agonist complex]] |
| - | [[Category: | + | [[Category: Glur2]] |
| - | [[Category: | + | [[Category: Ionotropic glutamate receptor]] |
| - | [[Category: | + | [[Category: Ligand binding core]] |
| - | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 00:39:08 2008'' | |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | |
Revision as of 21:39, 2 May 2008
X-RAY STRUCTURE OF THE GLUR2 LIGAND BINDING CORE (S1S2J) IN COMPLEX WITH Br-HIBO AT 1.65 A RESOLUTION
Overview
Glutamate is the principal excitatory neurotransmitter within the mammalian CNS, playing an important role in many different functions in the brain such as learning and memory. In this study, a combination of molecular biology, X-ray structure determinations, as well as electrophysiology and binding experiments, has been used to increase our knowledge concerning the ionotropic glutamate receptor GluR2 at the molecular level. Five high-resolution X-ray structures of the ligand-binding domain of GluR2 (S1S2J) complexed with the three agonists (S)-2-amino-3-[3-hydroxy-5-(2-methyl-2H-tetrazol-5-yl)isoxazol-4-yl]propio nic acid (2-Me-Tet-AMPA), (S)-2-amino-3-(3-carboxy-5-methylisoxazol-4-yl)propionic acid (ACPA), and (S)-2-amino-3-(4-bromo-3-hydroxy-isoxazol-5-yl)propionic acid (Br-HIBO), as well as of a mutant thereof (S1S2J-Y702F) in complex with ACPA and Br-HIBO, have been determined. The structures reveal that AMPA agonists with an isoxazole moiety adopt different binding modes in the receptor, dependent on the substituents of the isoxazole. Br-HIBO displays selectivity among different AMPA receptor subunits, and the design and structure determination of the S1S2J-Y702F mutant in complex with Br-HIBO and ACPA have allowed us to explain the molecular mechanism behind this selectivity and to identify key residues for ligand recognition. The agonists induce the same degree of domain closure as AMPA, except for Br-HIBO, which shows a slightly lower degree of domain closure. An excellent correlation between domain closure and efficacy has been obtained from electrophysiology experiments undertaken on non-desensitising GluR2i(Q)-L483Y receptors expressed in oocytes, providing strong evidence that receptor activation occurs as a result of domain closure. The structural results, combined with the functional studies on the full-length receptor, form a powerful platform for the design of new selective agonists.
About this Structure
1M5C is a Single protein structure of sequence from Rattus norvegicus. Full crystallographic information is available from OCA.
Reference
Structural basis for AMPA receptor activation and ligand selectivity: crystal structures of five agonist complexes with the GluR2 ligand-binding core., Hogner A, Kastrup JS, Jin R, Liljefors T, Mayer ML, Egebjerg J, Larsen IK, Gouaux E, J Mol Biol. 2002 Sep 6;322(1):93-109. PMID:12215417 Page seeded by OCA on Sat May 3 00:39:08 2008
