View source for 7f3o


==Crystal structure of the GluA2o LBD in complex with glutamate and TAK-653==
<StructureSection load='7f3o' size='340' side='right'caption='[[7f3o]], [[Resolution|resolution]] 1.44&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7F3O OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7F3O 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]] 1.44&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=0YK:7-(4-cyclohexyloxyphenyl)-9-methyl-4$l^{6}-thia-1$l^{4},5,8-triazabicyclo[4.4.0]deca-1(10),6,8-triene+4,4-dioxide'>0YK</scene>, <scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=GLU:GLUTAMIC+ACID'>GLU</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</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=7f3o FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7f3o OCA], [https://pdbe.org/7f3o PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7f3o RCSB], [https://www.ebi.ac.uk/pdbsum/7f3o PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7f3o ProSAT]</span></td></tr>
</table>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Agonistic profiles of AMPA receptor (AMPA-R) potentiators may be associated with seizure risk and bell-shaped dose-response effects. Here, we report the pharmacological characteristics of a novel AMPA-R potentiator, TAK-653, which exhibits minimal agonistic properties. TAK-653 bound to the ligand binding domain of recombinant AMPA-R in a glutamate-dependent manner. TAK-653 strictly potentiated a glutamate-induced Ca(2+) influx in hGluA1i-expressing CHO cells through structural interference at Ser743 in GluA1. In primary neurons, TAK-653 augmented AMPA-induced Ca(2+) influx and AMPA-elicited currents via physiological AMPA-R with little agonistic effects. Interestingly, TAK-653 enhanced electrically evoked AMPA-R-mediated EPSPs more potently than AMPA (agonist) or LY451646 (AMPA-R potentiator with a prominent agonistic effect) in brain slices. Moreover, TAK-653 improved cognition for both working memory and recognition memory, while LY451646 did so only for recognition memory, and AMPA did not improve either. These data suggest that the facilitation of phasic AMPA-R activation by physiologically-released glutamate is the key to enhancing synaptic and cognitive functions, and nonselective activation of resting AMPA-Rs may negatively affect this process. Importantly, TAK-653 had a wide safety margin against convulsion; TAK-653 showed a 419-fold (plasma Cmax) and 1017-fold (AUC plasma) margin in rats. These findings provide insight into a therapeutically important aspect of AMPA-R potentiation.

Strictly regulated agonist-dependent activation of AMPA-R is the key characteristic of TAK-653 for robust synaptic responses and cognitive improvement.,Suzuki A, Kunugi A, Tajima Y, Suzuki N, Suzuki M, Toyofuku M, Kuno H, Sogabe S, Kosugi Y, Awasaki Y, Kaku T, Kimura H Sci Rep. 2021 Jul 15;11(1):14532. doi: 10.1038/s41598-021-93888-0. PMID:34267258<ref>PMID:34267258</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 7f3o" style="background-color:#fffaf0;"></div>

==See Also==
*[[Glutamate receptor 3D structures|Glutamate receptor 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Hirokawa A]]
[[Category: Igaki S]]
[[Category: Lane W]]
[[Category: Snell G]]
[[Category: Sogabe S]]
[[Category: Zama Y]]