4lz7

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{{STRUCTURE_4lz7| PDB=4lz7 | SCENE= }}
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==Crystal structures of GLuR2 ligand-binding-domain in complex with glutamate and positive allosteric modulators==
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===Crystal structures of GLuR2 ligand-binding-domain in complex with glutamate and positive allosteric modulators===
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<StructureSection load='4lz7' size='340' side='right' caption='[[4lz7]], [[Resolution|resolution]] 2.10&Aring;' scene=''>
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{{ABSTRACT_PUBMED_24215237}}
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== Structural highlights ==
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<table><tr><td colspan='2'>[[4lz7]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/Buffalo_rat Buffalo rat]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4LZ7 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4LZ7 FirstGlance]. <br>
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==Function==
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=1YW:N-({(5S)-3-[3-FLUORO-4-(PYRROLIDIN-1-YL)PHENYL]-4,5-DIHYDRO-1,2-OXAZOL-5-YL}METHYL)ACETAMIDE'>1YW</scene>, <scene name='pdbligand=GLU:GLUTAMIC+ACID'>GLU</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4lz5|4lz5]], [[4lz8|4lz8]]</td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">Gria2, Glur2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10116 Buffalo rat])</td></tr>
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<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=4lz7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4lz7 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4lz7 RCSB], [http://www.ebi.ac.uk/pdbsum/4lz7 PDBsum]</span></td></tr>
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</table>
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== 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>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Positive allosteric modulators ("potentiators") of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors (AMPAR) enhance excitatory neurotransmission and may improve the cognitive deficits associated with various neurological disorders. The dihydroisoxazole (DHI) series of AMPAR potentiators described herein originated from the identification of 7 by a high-throughput functional activity screen using mouse embryonic stem (mES) cell-derived neuronal precursors. Subsequent structure-based drug design using X-ray crystal structures of the ligand-binding domain of human GluA2 led to the discovery of both PF-04725379 (11), which in tritiated form became a novel ligand for characterizing the binding affinities of subsequent AMPAR potentiators in rat brain homogenate, and PF-04701475 (8a), a prototype used to explore AMPAR-mediated pharmacology in vivo. Lead series optimization provided 16a, a functionally potent compound lacking the potentially bioactivatable aniline within 8a, but retaining desirable in vitro ADME properties.
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Discovery and Characterization of a Novel Dihydroisoxazole Class of alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) Receptor Potentiators.,Patel NC, Schwarz J, Hou XJ, Hoover DJ, Xie L, Fliri AJ, Gallaschun RJ, Lazzaro JT, Bryce DK, Hoffmann WE, Hanks AN, McGinnis D, Marr ES, Gazard JL, Hajos M, Scialis RJ, Hurst RS, Shaffer CL, Pandit J, O'Donnell CJ J Med Chem. 2013 Nov 27;56(22):9180-91. doi: 10.1021/jm401274b. Epub 2013 Nov 11. PMID:24215237<ref>PMID:24215237</ref>
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==About this Structure==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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[[4lz7]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/Buffalo_rat Buffalo rat]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4LZ7 OCA].
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</div>
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==Reference==
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==See Also==
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<ref group="xtra">PMID:024215237</ref><references group="xtra"/><references/>
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*[[Ionotropic Glutamate Receptors|Ionotropic Glutamate Receptors]]
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== References ==
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<references/>
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__TOC__
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</StructureSection>
[[Category: Buffalo rat]]
[[Category: Buffalo rat]]
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[[Category: Pandit, J.]]
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[[Category: Pandit, J]]
[[Category: Allosteric modulator]]
[[Category: Allosteric modulator]]
[[Category: Ampa receptor]]
[[Category: Ampa receptor]]
[[Category: Transport protein]]
[[Category: Transport protein]]

Revision as of 01:16, 25 December 2014

Crystal structures of GLuR2 ligand-binding-domain in complex with glutamate and positive allosteric modulators

4lz7, resolution 2.10Å

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