4iy6: Difference between revisions
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==Crystal structure of the GLUA2 ligand-binding domain (S1S2J-L483Y-N754S) in complex with glutamate and ME-CX516 at 1.72 A resolution== | |||
<StructureSection load='4iy6' size='340' side='right' caption='[[4iy6]], [[Resolution|resolution]] 1.72Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4iy6]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Rattus_norvegicus Rattus norvegicus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4IY6 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4IY6 FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GLU:GLUTAMIC+ACID'>GLU</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MQR:[(3R)-3-METHYLPIPERIDIN-1-YL](QUINOXALIN-6-YL)METHANONE'>MQR</scene>, <scene name='pdbligand=MQS:[(3S)-3-METHYLPIPERIDIN-1-YL](QUINOXALIN-6-YL)METHANONE'>MQS</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> | |||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3tdj|3tdj]], [[3tdk|3tdk]], [[2al5|2al5]], [[2al4|2al4]], [[4iy5|4iy5]]</td></tr> | |||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">Glur2, Gria2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10116 Rattus norvegicus])</td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4iy6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4iy6 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4iy6 RCSB], [http://www.ebi.ac.uk/pdbsum/4iy6 PDBsum]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Positive allosteric modulators of the ionotropic glutamate receptor A2 (GluA2) can serve as lead compounds for the development of cognitive enhancers. Several benzamide-type (S)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) receptor modulators such as aniracetam, CX516 and CX614 have been shown to inhibit the deactivation of AMPA receptors with a less pronounced effect on desensitization. Despite CX516 being an extensively investigated AMPA receptor modulator and one of the few clinically evaluated compounds, the binding mode of CX516 to AMPA receptors has not been reported. Here, the structures of a GluA2 ligand-binding domain mutant in complex with CX516 and the 3-methylpiperidine analogue of CX516 (Me-CX516) are reported. The structures show that the binding modes of CX516 and Me-CX516 are similar to those of aniracetam and CX614 and that there is limited space for substitution at the piperidine ring of CX516. The results therefore support that CX516, like aniracetam and CX614, modulates deactivation of AMPA receptors. | |||
Structural analysis of the positive AMPA receptor modulators CX516 and Me-CX516 in complex with the GluA2 ligand-binding domain.,Krintel C, Harpsoe K, Zachariassen LG, Peters D, Frydenvang K, Pickering DS, Gajhede M, Kastrup JS Acta Crystallogr D Biol Crystallogr. 2013 Sep 1;69(Pt 9):1645-52. doi:, 10.1107/S0907444913011839. Epub 2013 Aug 15. PMID:23999288<ref>PMID:23999288</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
== | ==See Also== | ||
*[[Ionotropic Glutamate Receptors|Ionotropic Glutamate Receptors]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Rattus norvegicus]] | [[Category: Rattus norvegicus]] | ||
[[Category: Frydenvang, K | [[Category: Frydenvang, K]] | ||
[[Category: Gajhede, M | [[Category: Gajhede, M]] | ||
[[Category: Harpsoe, K | [[Category: Harpsoe, K]] | ||
[[Category: Kastrup, J S | [[Category: Kastrup, J S]] | ||
[[Category: Krintel, C | [[Category: Krintel, C]] | ||
[[Category: Allosteric modulation]] | [[Category: Allosteric modulation]] | ||
[[Category: Ampa receptor ligand-binding domain]] | [[Category: Ampa receptor ligand-binding domain]] |
Revision as of 15:39, 21 December 2014
Crystal structure of the GLUA2 ligand-binding domain (S1S2J-L483Y-N754S) in complex with glutamate and ME-CX516 at 1.72 A resolutionCrystal structure of the GLUA2 ligand-binding domain (S1S2J-L483Y-N754S) in complex with glutamate and ME-CX516 at 1.72 A resolution
Structural highlights
Publication Abstract from PubMedPositive allosteric modulators of the ionotropic glutamate receptor A2 (GluA2) can serve as lead compounds for the development of cognitive enhancers. Several benzamide-type (S)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) receptor modulators such as aniracetam, CX516 and CX614 have been shown to inhibit the deactivation of AMPA receptors with a less pronounced effect on desensitization. Despite CX516 being an extensively investigated AMPA receptor modulator and one of the few clinically evaluated compounds, the binding mode of CX516 to AMPA receptors has not been reported. Here, the structures of a GluA2 ligand-binding domain mutant in complex with CX516 and the 3-methylpiperidine analogue of CX516 (Me-CX516) are reported. The structures show that the binding modes of CX516 and Me-CX516 are similar to those of aniracetam and CX614 and that there is limited space for substitution at the piperidine ring of CX516. The results therefore support that CX516, like aniracetam and CX614, modulates deactivation of AMPA receptors. Structural analysis of the positive AMPA receptor modulators CX516 and Me-CX516 in complex with the GluA2 ligand-binding domain.,Krintel C, Harpsoe K, Zachariassen LG, Peters D, Frydenvang K, Pickering DS, Gajhede M, Kastrup JS Acta Crystallogr D Biol Crystallogr. 2013 Sep 1;69(Pt 9):1645-52. doi:, 10.1107/S0907444913011839. Epub 2013 Aug 15. PMID:23999288[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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