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4U4X

Crystal structure of the GluA2 ligand-binding domain (S1S2J-L483Y-N754S) in complex with glutamate and BPAM37 at 1.56 A resolution.

Summary for 4U4X
Entry DOI10.2210/pdb4u4x/pdb
Related3TDJ 4N07
DescriptorGlutamate receptor 2,Glutamate receptor 2, 4-ethyl-3,4-dihydro-2H-pyrido[3,2-e][1,2,4]thiadiazine 1,1-dioxide, SULFATE ION, ... (8 entities in total)
Functional Keywordsampa receptor ligand-binding domain, bpam37 allosteric modulation, membrane protein
Biological sourceRattus norvegicus (Rat)
More
Cellular locationCell membrane ; Multi-pass membrane protein : P19491
Total number of polymer chains2
Total formula weight60415.14
Authors
Noerholm, A.B.,Frydenvang, K.,Kastrup, J.S. (deposition date: 2014-07-24, release date: 2014-11-19, Last modification date: 2024-11-20)
Primary citationFrancotte, P.,Nrholm, A.B.,Deva, T.,Olsen, L.,Frydenvang, K.,Goffin, E.,Fraikin, P.,de Tullio, P.,Challal, S.,Thomas, J.Y.,Iop, F.,Louis, C.,Botez-Pop, I.,Lestage, P.,Danober, L.,Kastrup, J.S.,Pirotte, B.
Positive Allosteric Modulators of 2-Amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic Acid Receptors Belonging to 4-Cyclopropyl-3,4-dihydro-2H-1,2,4-pyridothiadiazine Dioxides and Diversely Chloro-Substituted 4-Cyclopropyl-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-Dioxides.
J.Med.Chem., 57:9539-9553, 2014
Cited by
PubMed Abstract: Two 4-ethyl-substituted pyridothiadiazine dioxides belonging to α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor positive allosteric modulators were cocrystallized with the GluA2 ligand binding domain in order to decipher the impact of the position of the nitrogen atom on their binding mode at the AMPA receptors. The latter was found to be very similar to that of previously described benzothiadiazine-type AMPA receptor modulators. The affinity of the two compounds for the receptor was determined by isothermal titration calorimetry. Accordingly, the synthesis and biological evaluation of novel 4-cyclopropyl-substituted pyridothiadiazine dioxides was performed and completed with the synthesis of the corresponding chloro-substituted 4-cyclopropyl-3,4-dihydro-2H-benzothiadiazine 1,1-dioxides. The "8-aza" compound 32 was found to be the most potent pyridothiadiazine-type AMPA receptor potentiator in vitro, whereas the 7-chloro-substituted compound 36c emerged as the most promising benzothiadiazine dioxide. Due to proper drug-likeness and low in vivo acute toxicity in mice, 36c was chosen for a more complete preclinical evaluation. The compound was able to easily cross the blood-brain barrier. In an in vivo object recognition test with CD1 mice, oral administration of 36c was found to significantly improve cognition performance at doses as low as 1 mg/kg.
PubMed: 25375781
DOI: 10.1021/jm501268r
PDB entries with the same primary citation
Experimental method
X-RAY DIFFRACTION (1.56 Å)
Structure validation

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