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<StructureSection load='6zyu' size='340' side='right'caption='[[6zyu]], [[Resolution|resolution]] 1.90&Aring;' scene=''>
<StructureSection load='6zyu' size='340' side='right'caption='[[6zyu]], [[Resolution|resolution]] 1.90&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[6zyu]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Rattus_norvegicus Rattus norvegicus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6ZYU OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6ZYU FirstGlance]. <br>
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6ZYU OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6ZYU FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.9&#8491;</td></tr>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.9&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=CAC:CACODYLATE+ION'>CAC</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=GLU:GLUTAMIC+ACID'>GLU</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=QSW:(4~{R})-4-cyclopropyl-7-fluoranyl-3,4-dihydro-2~{H}-thiochromene+1,1-dioxide'>QSW</scene>, <scene name='pdbligand=QSZ:(4~{S})-4-cyclopropyl-7-fluoranyl-3,4-dihydro-2~{H}-thiochromene+1,1-dioxide'>QSZ</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=CAC:CACODYLATE+ION'>CAC</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=GLU:GLUTAMIC+ACID'>GLU</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=QSW:(4~{R})-4-cyclopropyl-7-fluoranyl-3,4-dihydro-2~{H}-thiochromene+1,1-dioxide'>QSW</scene>, <scene name='pdbligand=QSZ:(4~{S})-4-cyclopropyl-7-fluoranyl-3,4-dihydro-2~{H}-thiochromene+1,1-dioxide'>QSZ</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6zyu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6zyu OCA], [https://pdbe.org/6zyu PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6zyu RCSB], [https://www.ebi.ac.uk/pdbsum/6zyu PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6zyu ProSAT]</span></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6zyu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6zyu OCA], [https://pdbe.org/6zyu PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6zyu RCSB], [https://www.ebi.ac.uk/pdbsum/6zyu PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6zyu ProSAT]</span></td></tr>
</table>
</table>
== Function ==
[https://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 ==
On the basis of the activity of 1,2,4-benzothiadiazine 1,1-dioxides as positive allosteric modulators of AMPA receptors, thiochroman 1,1-dioxides were designed applying the isosteric replacement concept. The new compounds expressed strong modulatory activity on AMPA receptors in vitro, although lower than their corresponding benzothiadiazine analogues. The pharmacokinetic profile of three thiochroman 1,1-dioxides (12a, 12b, 12e) was examined in vivo after oral administration, showing that these compounds freely cross the blood-brain barrier. Structural analysis was achieved using X-ray crystallography after cocrystallization of the racemic compound 12b in complex with the ligand-binding domain of GluA2 (L504Y/N775S). Interestingly, both enantiomers of 12b were found to interact with the GluA2 dimer interface, almost identically to its benzothiadiazine analogue, BPAM344 (4). The interactions of the two enantiomers in the cocrystal were further analyzed (mapping Hirshfeld surfaces and 2D fingerprint) and compared to those of 4. Taken together, these data explain the lower affinity on AMPA receptors of thiochroman 1,1-dioxides compared to their corresponding 1,2,4-benzothiadiazine 1,1-dioxides.
Development of Thiochroman Dioxide Analogues of Benzothiadiazine Dioxides as New Positive Allosteric Modulators of alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptors.,Etse KS, Dorosz J, McLain Christensen K, Thomas JY, Botez Pop I, Goffin E, Colson T, Lestage P, Danober L, Pirotte B, Kastrup JS, Francotte P ACS Chem Neurosci. 2021 Jul 21;12(14):2679-2692. doi:, 10.1021/acschemneuro.1c00255. Epub 2021 Jul 9. PMID:34242002<ref>PMID:34242002</ref>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6zyu" style="background-color:#fffaf0;"></div>


==See Also==
==See Also==
*[[Glutamate receptor 3D structures|Glutamate receptor 3D structures]]
*[[Glutamate receptor 3D structures|Glutamate receptor 3D structures]]
== References ==
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Large Structures]]
[[Category: Large Structures]]
[[Category: Rattus norvegicus]]
[[Category: Christensen KM]]
[[Category: Christensen KM]]
[[Category: Dorosz J]]
[[Category: Dorosz J]]
[[Category: Kastrup JS]]
[[Category: Kastrup JS]]

Latest revision as of 10:48, 23 October 2024

Structure of the GluA2 ligand-binding domain (L483Y-N754S) in complex with glutamate and BPAM549

6zyu, resolution 1.90Å

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