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5zg2

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Revision as of 06:56, 27 March 2019

Crystal structure of the GluA2o LBD in complex with ZK200775 and Compound-2

Structural highlights

5zg2 is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, , , ,
Gene:	GLUR2 (HUMAN)
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[GRIA2_HUMAN] Receptor for glutamate that functions as ligand-gated ion channel in the central nervous system and plays an important role in excitatory synaptic transmission. L-glutamate acts as an excitatory neurotransmitter at many synapses in the central nervous system. Binding of the excitatory neurotransmitter L-glutamate induces a conformation change, leading to the opening of the cation channel, and thereby converts the chemical signal to an electrical impulse. The receptor then desensitizes rapidly and enters a transient inactive state, characterized by the presence of bound agonist. In the presence of CACNG4 or CACNG7 or CACNG8, shows resensitization which is characterized by a delayed accumulation of current flux upon continued application of glutamate.^[1]

Publication Abstract from PubMed

Activation of alpha-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.

TAK-137, an AMPA-R potentiator with little agonistic effect, has a wide therapeutic window.,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 Neuropsychopharmacology. 2018 Sep 12. pii: 10.1038/s41386-018-0213-7. doi:, 10.1038/s41386-018-0213-7. PMID:30209408^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Ward SE, Harries M, Aldegheri L, Andreotti D, Ballantine S, Bax BD, Harris AJ, Harker AJ, Lund J, Melarange R, Mingardi A, Mookherjee C, Mosley J, Neve M, Oliosi B, Profeta R, Smith KJ, Smith PW, Spada S, Thewlis KM, Yusaf SP. Discovery of N-[(2S)-5-(6-Fluoro-3-pyridinyl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfo namide, a Novel Clinical AMPA Receptor Positive Modulator. J Med Chem. 2010 Jul 8. PMID:20614889 doi:10.1021/jm1005429
↑ 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. 2018 Sep 12. pii: 10.1038/s41386-018-0213-7. doi:, 10.1038/s41386-018-0213-7. PMID:30209408 doi:http://dx.doi.org/10.1038/s41386-018-0213-7

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5zg2"

@@ Line 1: / Line 1: @@
 ==Crystal structure of the GluA2o LBD in complex with ZK200775 and Compound-2==
-<StructureSection load='5zg2' size='340' side='right' caption='[[5zg2]], [[Resolution|resolution]] 1.25&Aring;' scene=''>
+<StructureSection load='5zg2' size='340' side='right'caption='[[5zg2]], [[Resolution|resolution]] 1.25&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5zg2]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5ZG2 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5ZG2 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5zg2]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5ZG2 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5ZG2 FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=9C0:9-(4-~{tert}-butylphenyl)-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine+2,2-dioxide'>9C0</scene>, <scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=ZK1:{[7-MORPHOLIN-4-YL-2,3-DIOXO-6-(TRIFLUOROMETHYL)-3,4-DIHYDROQUINOXALIN-1(2H)-YL]METHYL}PHOSPHONIC+ACID'>ZK1</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">GLUR2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
 <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5zg2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5zg2 OCA], [http://pdbe.org/5zg2 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5zg2 RCSB], [http://www.ebi.ac.uk/pdbsum/5zg2 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5zg2 ProSAT]</span></td></tr>
 </table>
@@ Line 22: / Line 23: @@
 __TOC__
 </StructureSection>
+[[Category: Human]]
+[[Category: Large Structures]]
 [[Category: Hirokawa, A]]
 [[Category: Igaki, S]]

5zg2

From Proteopedia

Revision as of 06:56, 27 March 2019

Crystal structure of the GluA2o LBD in complex with ZK200775 and Compound-2

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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