7F3O

Crystal structure of the GluA2o LBD in complex with glutamate and TAK-653

Summary for 7F3O

• Entry DOI: 10.2210/pdb7f3o/pdb
• Descriptor: Glutamate receptor 2, GLUTAMIC ACID, 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, ... (7 entities in total)
• Functional Keywords: ampa receptor ligand-binding domain, allosteric modulation complex, membrane protein, transport protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 6
• Total formula weight: 179104.62

Authors

Sogabe, S.,Igaki, S.,Hirokawa, A.,Zama, Y.,Lane, W.,Snell, G. (deposition date: 2021-06-16, release date: 2021-07-28, Last modification date: 2024-11-06)

Primary citation

Suzuki, A.,Kunugi, A.,Tajima, Y.,Suzuki, N.,Suzuki, M.,Toyofuku, M.,Kuno, H.,Sogabe, S.,Kosugi, Y.,Awasaki, Y.,Kaku, T.,Kimura, H.
Strictly regulated agonist-dependent activation of AMPA-R is the key characteristic of TAK-653 for robust synaptic responses and cognitive improvement.
Sci Rep, 11:14532-14532, 2021

PubMed Abstract: 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 influx in hGluA1i-expressing CHO cells through structural interference at Ser743 in GluA1. In primary neurons, TAK-653 augmented AMPA-induced Ca 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 C) and 1017-fold (AUC ) margin in rats. These findings provide insight into a therapeutically important aspect of AMPA-R potentiation.

PubMed: 34267258
DOI: 10.1038/s41598-021-93888-0

Experimental method

X-RAY DIFFRACTION (1.44 Å)