5ybf
From Proteopedia
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| - | '''Unreleased structure''' | ||
| - | + | ==Crystal structure of the GluA2o LBD in complex with glutamate and HBT1== | |
| + | <StructureSection load='5ybf' size='340' side='right' caption='[[5ybf]], [[Resolution|resolution]] 1.50Å' 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> | ||
| + | </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='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> | ||
| + | == 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> |
| - | [[Category: | + | <div class="pdbe-citations 5ybf" style="background-color:#fffaf0;"></div> |
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Hirokawa, A]] | ||
| + | [[Category: Igaki, S]] | ||
[[Category: Lane, W]] | [[Category: Lane, W]] | ||
| + | [[Category: Snell, G]] | ||
[[Category: Sogabe, S]] | [[Category: Sogabe, S]] | ||
| - | [[Category: Hirokawa, A]] | ||
[[Category: Zama, Y]] | [[Category: Zama, Y]] | ||
| - | [[Category: | + | [[Category: Allosteric modulation complex]] |
| + | [[Category: Ampa receptor ligand-binding domain]] | ||
| + | [[Category: Membrane protein]] | ||
| + | [[Category: Transport protein]] | ||
Revision as of 06:58, 17 January 2018
Crystal structure of the GluA2o LBD in complex with glutamate and HBT1
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