5ybg: Difference between revisions
From Proteopedia
Jump to navigationJump to search
m Protected "5ybg" [edit=sysop:move=sysop] |
No edit summary |
||
| Line 1: | Line 1: | ||
The | ==Crystal structure of the GluA2o LBD in complex with glutamate and LY451395== | ||
<StructureSection load='5ybg' size='340' side='right' caption='[[5ybg]], [[Resolution|resolution]] 1.52Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[5ybg]] is a 6 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5YBG OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5YBG FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=8SO:N-[(2R)-2-[4-[4-[2-(methylsulfonylamino)ethyl]phenyl]phenyl]propyl]propane-2-sulfonamide'>8SO</scene>, <scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=GLU:GLUTAMIC+ACID'>GLU</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</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=5ybg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ybg OCA], [http://pdbe.org/5ybg PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5ybg RCSB], [http://www.ebi.ac.uk/pdbsum/5ybg PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5ybg 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> | |||
<div style="background-color:#fffaf0;"> | |||
== 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<ref>PMID:29298820</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 5ybg" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Hirokawa, A]] | |||
[[Category: Igaki, S]] | |||
[[Category: Lane, W]] | |||
[[Category: Snell, G]] | [[Category: Snell, G]] | ||
[[Category: Sogabe, S]] | [[Category: Sogabe, S]] | ||
[[Category: Zama, Y]] | [[Category: Zama, Y]] | ||
[[Category: | [[Category: Allosteric modulation complex]] | ||
[[Category: Ampa receptor ligand-binding domain]] | |||
[[Category: Membrane protein]] | |||
[[Category: Transport protein]] | |||
