5zg3

From Proteopedia

(Difference between revisions)

Current revision

Crystal structure of the GluA2o LBD in complex with glutamate and TAK-137

Structural highlights

5zg3 is a 6 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.65Å
Ligands:	, , ,
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 See Also
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5zg3"

@@ Line 3: / Line 3: @@
 <StructureSection load='5zg3' size='340' side='right'caption='[[5zg3]], [[Resolution|resolution]] 1.65&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5zg3]] is a 6 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=5ZG3 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5ZG3 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5zg3]] is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5ZG3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5ZG3 FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=9C6:9-(4-phenoxyphenyl)-3,4-dihydro-2H-2lambda~6~-pyrido[2,1-c][1,2,4]thiadiazine-2,2-dione'>9C6</scene>, <scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=GLU:GLUTAMIC+ACID'>GLU</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.65&#8491;</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='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=9C6:9-(4-phenoxyphenyl)-3,4-dihydro-2H-2lambda~6~-pyrido[2,1-c][1,2,4]thiadiazine-2,2-dione'>9C6</scene>, <scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=GLU:GLUTAMIC+ACID'>GLU</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></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=5zg3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5zg3 OCA], [http://pdbe.org/5zg3 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5zg3 RCSB], [http://www.ebi.ac.uk/pdbsum/5zg3 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5zg3 ProSAT]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5zg3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5zg3 OCA], [https://pdbe.org/5zg3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5zg3 RCSB], [https://www.ebi.ac.uk/pdbsum/5zg3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5zg3 ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[http://www.uniprot.org/uniprot/GRIA2_HUMAN 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.<ref>PMID:20614889</ref>
+[https://www.uniprot.org/uniprot/GRIA2_HUMAN 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.<ref>PMID:20614889</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 19: / Line 19: @@
 </div>
 <div class="pdbe-citations 5zg3" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Glutamate receptor 3D structures|Glutamate receptor 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Hirokawa, A]]
+[[Category: Hirokawa A]]
-[[Category: Igaki, S]]
+[[Category: Igaki S]]
-[[Category: Lane, W]]
+[[Category: Lane W]]
-[[Category: Snell, G]]
+[[Category: Snell G]]
-[[Category: Sogabe, S]]
+[[Category: Sogabe S]]
-[[Category: Zama, Y]]
+[[Category: Zama Y]]
-[[Category: Allosteric modulation complex]]
-[[Category: Ampa receptor ligand-binding domain]]
-[[Category: Membrane protein]]
-[[Category: Transport protein]]

5zg3

From Proteopedia

Current revision

Crystal structure of the GluA2o LBD in complex with glutamate and TAK-137

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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