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PDBsum entry 5zg0
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Transport protein
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PDB id
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5zg0
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PDB id:
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| Name: |
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Transport protein
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Title:
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Crystal structure of the glua2o lbd in complex with glutamate and compound-1
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Structure:
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Glutamate receptor 2. Chain: a, b, c, d, e, f. Fragment: unp residues 413-527,unp residues 653-796. Synonym: glur-2,ampa-selective glutamate receptor 2,glur-b,glur-k2, glutamate receptor ionotropic,ampa 2,glua2. Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: glur2, gria2, glur2. Expressed in: escherichia coli. Expression_system_taxid: 562
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Resolution:
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1.58Å
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R-factor:
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0.195
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R-free:
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0.221
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Authors:
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S.Sogabe,S.Igaki,A.Hirokawa,Y.Zama,W.Lane,G.Snell
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Key ref:
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A.Kunugi
et al.
(2019).
TAK-137, an AMPA-R potentiator with little agonistic effect, has a wide therapeutic window.
Neuropsychopharmacology,
44,
961-970.
PubMed id:
DOI:
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Date:
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07-Mar-18
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Release date:
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16-Jan-19
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PROCHECK
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Headers
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References
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P42262
(GRIA2_HUMAN) -
Glutamate receptor 2 from Homo sapiens
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Seq:
Struc:
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883 a.a.
260 a.a.*
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Key: |
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PfamA domain |
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Secondary structure |
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*
PDB and UniProt seqs differ
at 2 residue positions (black
crosses)
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DOI no:
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Neuropsychopharmacology
44:961-970
(2019)
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PubMed id:
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TAK-137, an AMPA-R potentiator with little agonistic effect, has a wide therapeutic window.
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A.Kunugi,
M.Tanaka,
A.Suzuki,
Y.Tajima,
N.Suzuki,
M.Suzuki,
S.Nakamura,
H.Kuno,
A.Yokota,
S.Sogabe,
Y.Kosugi,
Y.Awasaki,
T.Kaku,
H.Kimura.
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ABSTRACT
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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.
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Links
