4isu
From Proteopedia
(Difference between revisions)
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| - | + | ==Crystal structure of the GluA2 ligand-binding domain (S1S2J) in complex with the antagonist (2R)-IKM-159 at 2.3A resolution.== | |
| - | + | <StructureSection load='4isu' size='340' side='right' caption='[[4isu]], [[Resolution|resolution]] 2.30Å' scene=''> | |
| - | + | == Structural highlights == | |
| - | + | <table><tr><td colspan='2'>[[4isu]] is a 4 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=4ISU OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4ISU FirstGlance]. <br> | |
| - | ==Function== | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=IKM:(4AS,5AR,6R,8AS,8BS)-5A-(CARBOXYMETHYL)-8-OXO-2,4A,5A,6,7,8,8A,8B-OCTAHYDRO-1H-PYRROLO[3,4 4,5]FURO[3,2-B]PYRIDINE-6-CARBOXYLIC+ACID'>IKM</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></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=4isu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4isu OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4isu RCSB], [http://www.ebi.ac.uk/pdbsum/4isu PDBsum]</span></td></tr> | ||
| + | </table> | ||
| + | == Function == | ||
[[http://www.uniprot.org/uniprot/GRIA2_RAT GRIA2_RAT]] Receptor for glutamate that functions as ligand-gated ion channel in the central nervous system and plays an important role in excitatory synaptic transmission. L-glutamate acts as an excitatory neurotransmitter at many synapses in the central nervous system. Binding of the excitatory neurotransmitter L-glutamate induces a conformation change, leading to the opening of the cation channel, and thereby converts the chemical signal to an electrical impulse. The receptor then desensitizes rapidly and enters a transient inactive state, characterized by the presence of bound agonist. In the presence of CACNG4 or CACNG7 or CACNG8, shows resensitization which is characterized by a delayed accumulation of current flux upon continued application of glutamate.<ref>PMID:9351977</ref> <ref>PMID:19265014</ref> <ref>PMID:21172611</ref> <ref>PMID:12501192</ref> <ref>PMID:12015593</ref> <ref>PMID:12872125</ref> <ref>PMID:12730367</ref> <ref>PMID:16192394</ref> <ref>PMID:15591246</ref> <ref>PMID:17018279</ref> <ref>PMID:16483599</ref> <ref>PMID:19946266</ref> <ref>PMID:21317873</ref> <ref>PMID:21846932</ref> | [[http://www.uniprot.org/uniprot/GRIA2_RAT GRIA2_RAT]] Receptor for glutamate that functions as ligand-gated ion channel in the central nervous system and plays an important role in excitatory synaptic transmission. L-glutamate acts as an excitatory neurotransmitter at many synapses in the central nervous system. Binding of the excitatory neurotransmitter L-glutamate induces a conformation change, leading to the opening of the cation channel, and thereby converts the chemical signal to an electrical impulse. The receptor then desensitizes rapidly and enters a transient inactive state, characterized by the presence of bound agonist. In the presence of CACNG4 or CACNG7 or CACNG8, shows resensitization which is characterized by a delayed accumulation of current flux upon continued application of glutamate.<ref>PMID:9351977</ref> <ref>PMID:19265014</ref> <ref>PMID:21172611</ref> <ref>PMID:12501192</ref> <ref>PMID:12015593</ref> <ref>PMID:12872125</ref> <ref>PMID:12730367</ref> <ref>PMID:16192394</ref> <ref>PMID:15591246</ref> <ref>PMID:17018279</ref> <ref>PMID:16483599</ref> <ref>PMID:19946266</ref> <ref>PMID:21317873</ref> <ref>PMID:21846932</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | IKM-159 was developed and identified as a member of a new class of heterotricyclic glutamate analogues that act as AMPA receptor-selective antagonists. However, it was not known which enantiomer of IKM-159 was responsible for its pharmacological activities. Here, we report in vivo and in vitro neuronal activities of both enantiomers of IKM-159 prepared by enantioselective asymmetric synthesis. By employment of (R)-2-amino-2-(4-methoxyphenyl)ethanol as a chiral auxiliary, (2R)-IKM-159 and the (2S)-counterpart were successfully synthesized in 0.70% and 1.5% yields, respectively, over a total of 18 steps. Both behavioral and electrophysiological assays showed that the biological activity observed for the racemic mixture was reproduced only with (2R)-IKM-159, whereas the (2S)-counterpart was inactive in both assays. Racemic IKM-159 was crystallized with the ligand-binding domain of GluA2, and the structure revealed a complex containing (2R)-IKM-159 at the glutamate binding site. (2R)-IKM-159 locks the GluA2 in an open form, consistent with a pharmacological action as competitive antagonist of AMPA receptors. | ||
| + | |||
| + | 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.,Juknaite L, Sugamata Y, Tokiwa K, Ishikawa Y, Takamizawa S, Eng A, Sakai R, Pickering DS, Frydenvang K, Swanson GT, Kastrup JS, Oikawa M J Med Chem. 2013 Mar 13. PMID:23432124<ref>PMID:23432124</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: Juknaite, L | + | [[Category: Juknaite, L]] |
| - | [[Category: Kastrup, J S | + | [[Category: Kastrup, J S]] |
[[Category: Ampa receptor ligand-binding domain]] | [[Category: Ampa receptor ligand-binding domain]] | ||
[[Category: Antagonist]] | [[Category: Antagonist]] | ||
Revision as of 08:01, 25 December 2014
Crystal structure of the GluA2 ligand-binding domain (S1S2J) in complex with the antagonist (2R)-IKM-159 at 2.3A resolution.
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