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5ybf

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Revision as of 08:24, 22 February 2018

Crystal structure of the GluA2o LBD in complex with glutamate and HBT1

Structural highlights

5ybf is a 6 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:	GRIA2, 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

Alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor (AMPA-R) potentiators with brain-derived neurotrophic factor (BDNF)-induction potential could be promising as therapeutic drugs for neuropsychiatric and neurological disorders. However, AMPA-R potentiators such as LY451646 have risks of narrow bell-shaped responses in pharmacological effects, including in vivo BDNF induction. Interestingly, LY451646 and LY451395, other AMPA-R potentiators, showed agonistic effects and exhibited bell-shaped responses in the BDNF production in primary neurons. We hypothesized that the agonistic property is related to the bell-shaped response and endeavored to discover novel AMPA-R potentiators with lower agonistic effects. LY451395 showed an agonistic effect in primary neurons, but not in a cell line expressing AMPA-Rs, in Ca2+ influx assays; thus, we used a Ca2+ influx assay in primary neurons and, from a chemical library, discovered two AMPA-R potentiators with lower agonistic effects: 2-(((5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetyl)amino)-4,5,6,7-tetrahydr o-1-benzothiophene-3-carboxamide (HBT1) and (3S)-1-(4-tert-butylphenyl)-N-((1R)-2-(dimethylamino)-1-phenylethyl)-3-isobutyl-2 -oxopyrrolidine-3-carboxamide (OXP1). In a patch-clamp study using primary neurons, HBT1 showed little agonistic effect, while both LY451395 and OXP1 showed remarkable agonistic effects. HBT1, but not OXP1, did not show remarkable bell-shaped response in BDNF production in primary neurons. HBT1 bound to the ligand-binding domain (LBD) of AMPA-R in a glutamate-dependent manner. The mode of HBT1 and LY451395 binding to a pocket in the LBD of AMPA-R differed: HBT1, but not LY451395, formed hydrogen bonds with S518 in the LBD. OXP1 may bind to a cryptic binding pocket on AMPA-R. Lower agonistic profile of HBT1 may associate with its lower risks of bell-shaped responses in BDNF production in primary neurons.

HBT1, a novel AMPA receptor potentiator with lower agonistic effect, avoided bell-shaped response in in vitro BDNF production.,Kunugi A, Tajima Y, Kuno H, Sogabe S, Kimura H J Pharmacol Exp Ther. 2018 Jan 3. pii: jpet.117.245050. doi:, 10.1124/jpet.117.245050. PMID:29298820^[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, Tajima Y, Kuno H, Sogabe S, Kimura H. HBT1, a novel AMPA receptor potentiator with lower agonistic effect, avoided bell-shaped response in in vitro BDNF production. J Pharmacol Exp Ther. 2018 Jan 3. pii: jpet.117.245050. doi:, 10.1124/jpet.117.245050. PMID:29298820 doi:http://dx.doi.org/10.1124/jpet.117.245050

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/5ybf"

@@ Line 3: / Line 3: @@
 <StructureSection load='5ybf' size='340' side='right' caption='[[5ybf]], [[Resolution|resolution]] 1.50&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5ybf]] is a 6 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5YBF OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5YBF FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5ybf]] 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=5YBF OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5YBF FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=8SR:2-[2-[5-methyl-3-(trifluoromethyl)pyrazol-1-yl]ethanoylamino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide'>8SR</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='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">GRIA2, 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=5ybf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ybf OCA], [http://pdbe.org/5ybf PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5ybf RCSB], [http://www.ebi.ac.uk/pdbsum/5ybf PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5ybf ProSAT]</span></td></tr>
 </table>
@@ Line 22: / Line 23: @@
 __TOC__
 </StructureSection>
+[[Category: Human]]
 [[Category: Hirokawa, A]]
 [[Category: Igaki, S]]

5ybf

From Proteopedia

Revision as of 08:24, 22 February 2018

Crystal structure of the GluA2o LBD in complex with glutamate and HBT1

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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