5ZG0

Crystal structure of the GluA2o LBD in complex with glutamate and Compound-1

Summary for 5ZG0

• Entry DOI: 10.2210/pdb5zg0/pdb
• Descriptor: Glutamate receptor 2, GLUTAMIC ACID, ZINC ION, ... (6 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: 179063.14

Authors

Sogabe, S.,Igaki, S.,Hirokawa, A.,Zama, Y.,Lane, W.,Snell, G. (deposition date: 2018-03-07, release date: 2019-01-16, Last modification date: 2024-10-23)

Primary citation

Kunugi, A.,Tanaka, M.,Suzuki, A.,Tajima, Y.,Suzuki, N.,Suzuki, M.,Nakamura, S.,Kuno, H.,Yokota, A.,Sogabe, S.,Kosugi, Y.,Awasaki, Y.,Kaku, T.,Kimura, H.
TAK-137, an AMPA-R potentiator with little agonistic effect, has a wide therapeutic window.
Neuropsychopharmacology, 44:961-970, 2019

PubMed Abstract: Activation of α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor (AMPA-R) is a promising strategy to treat psychiatric and neurological diseases if issues of bell-shaped response and narrow safety margin against seizure can be overcome. Here, we show that structural interference at Ser743 in AMPA-R is a key to lower the agonistic effect of AMPA-R potentiators containing dihydropyridothiadiazine 2,2-dioxides skeleton. With this structural insight, TAK-137, 9-(4-phenoxyphenyl)-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide, was discovered as a novel AMPA-R potentiator with a lower agonistic effect than an AMPA-R potentiator LY451646 ((R)-N-(2-(4'-cyanobiphenyl-4-yl)propyl)propane-2-sulfonamide) in rat primary neurons. TAK-137 induced brain-derived neurotrophic factor in neurons in rodents and potently improved cognition in both rats and monkeys. Compared to LY451646, TAK-137 had a wider safety margin against seizure in rats. TAK-137 enhanced neural progenitor proliferation over a broader range of doses in rodents. Thus, TAK-137 is a promising AMPA-R potentiator with potent procognitive effects and lower risks of bell-shaped response and seizure. These data may open the door for the development of AMPA-R potentiators as therapeutic drugs for psychiatric and neurological diseases.

PubMed: 30209408
DOI: 10.1038/s41386-018-0213-7

Experimental method

X-RAY DIFFRACTION (1.58 Å)