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| | ==Structure of GluK1 ligand-binding domain (S1S2) in complex with LM-12b at 2.05 A resolution== | | ==Structure of GluK1 ligand-binding domain (S1S2) in complex with LM-12b at 2.05 A resolution== |
| - | <StructureSection load='5neb' size='340' side='right' caption='[[5neb]], [[Resolution|resolution]] 2.05Å' scene=''> | + | <StructureSection load='5neb' size='340' side='right'caption='[[5neb]], [[Resolution|resolution]] 2.05Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5neb]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Buffalo_rat Buffalo rat]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5NEB OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5NEB FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5neb]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Rattus_norvegicus Rattus norvegicus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5NEB OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5NEB FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=8VE:(3~{a}~{R},4~{S},6~{a}~{R})-1-methyl-4,5,6,6~{a}-tetrahydro-3~{a}~{H}-pyrrolo[3,4-c]pyrazole-3,4-dicarboxylic+acid'>8VE</scene>, <scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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]] 2.05Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">Grik1, Glur5 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10116 Buffalo rat])</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=8VE:(3~{a}~{R},4~{S},6~{a}~{R})-1-methyl-4,5,6,6~{a}-tetrahydro-3~{a}~{H}-pyrrolo[3,4-c]pyrazole-3,4-dicarboxylic+acid'>8VE</scene>, <scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=5neb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5neb OCA], [http://pdbe.org/5neb PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5neb RCSB], [http://www.ebi.ac.uk/pdbsum/5neb PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5neb 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=5neb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5neb OCA], [https://pdbe.org/5neb PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5neb RCSB], [https://www.ebi.ac.uk/pdbsum/5neb PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5neb ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/GRIK1_RAT GRIK1_RAT]] Ionotropic glutamate receptor. 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. May be involved in the transmission of light information from the retina to the hypothalamus.<ref>PMID:16540562</ref> | + | [https://www.uniprot.org/uniprot/GRIK1_RAT GRIK1_RAT] Ionotropic glutamate receptor. 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. May be involved in the transmission of light information from the retina to the hypothalamus.<ref>PMID:16540562</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 5neb" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 5neb" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Glutamate receptor 3D structures|Glutamate receptor 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Buffalo rat]] | + | [[Category: Large Structures]] |
| - | [[Category: Frydenvang, K]] | + | [[Category: Rattus norvegicus]] |
| - | [[Category: Kastrup, J S]] | + | [[Category: Frydenvang K]] |
| - | [[Category: Laulumaa, S]] | + | [[Category: Kastrup JS]] |
| - | [[Category: Moellerud, S]] | + | [[Category: Laulumaa S]] |
| - | [[Category: Agonist]] | + | [[Category: Moellerud S]] |
| - | [[Category: Gluk1]]
| + | |
| - | [[Category: Glur5]]
| + | |
| - | [[Category: Ionotropic glutamate receptor]]
| + | |
| - | [[Category: Kainate receptor]]
| + | |
| - | [[Category: Ligand-binding domain]]
| + | |
| - | [[Category: Membrane protein]]
| + | |
| Structural highlights
5neb is a 2 chain structure with sequence from Rattus norvegicus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Method: | X-ray diffraction, Resolution 2.05Å |
| Ligands: | , , , , |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
GRIK1_RAT Ionotropic glutamate receptor. 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. May be involved in the transmission of light information from the retina to the hypothalamus.[1]
Publication Abstract from PubMed
Ionotropic glutamate receptors (iGluRs) are involved in most of the fast excitatory synaptic transmission in the central nervous system. These receptors are important for learning and memory formation, but are also involved in the development of diseases such as Alzheimer's disease, epilepsy and depression. To understand the function of different types of iGluRs, selective agonists are invaluable as pharmacological tool compounds. Here, we report binding affinities of two bicyclic, conformationally restricted analogues of glutamate (CIP-AS and LM-12b) at AMPA (GluA2 and GluA3) and kainate receptor subunits (GluK1-3 and GluK5). Both CIP-AS and LM-12b were found to be GluK3-preferring agonists, with Ki of 6 and 22 nM, respectively, at recombinant GluK3 receptors. The detailed binding mode of CIP-AS and LM-12b in the ligand-binding domains of the AMPA receptor subunit GluA2 (GluA2-LBD) and the kainate receptor subunits GluK1 (GluK1-LBD) and GluK3 (GluK3-LBD) was investigated by X-ray crystallography. CIP-AS stabilized all three receptor constructs in conformations similar to those with kainate. Remarkably, whereas LM-12b bound in a similar manner to CIP-AS in GluA2-LBD and GluK3-LBD, it introduced full closure of the ligand-binding domain in GluK1-LBD and formation of a D1-D2 interlobe hydrogen bond between Glu441 and Ser721, as also observed with glutamate. As the binding affinity of LM-12b at GluK1 is approximately 8-fold better than that for CIP-AS (Ki of 85 and 656 nM, respectively), it shows that small changes in agonist structure can lead to prominent differences in structure and function.
Structure and Affinity of Two Bicyclic Glutamate Analogues at AMPA and Kainate Receptors.,Mollerud S, Pinto A, Marconi L, Frydenvang K, Thorsen TS, Laulumaa S, Venskutonyte R, Winther S, Moral AMC, Tamborini L, Conti P, Pickering DS, Kastrup JS ACS Chem Neurosci. 2017 Sep 20;8(9):2056-2064. doi: 10.1021/acschemneuro.7b00201., Epub 2017 Jul 21. PMID:28691798[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Mayer ML, Ghosal A, Dolman NP, Jane DE. Crystal structures of the kainate receptor GluR5 ligand binding core dimer with novel GluR5-selective antagonists. J Neurosci. 2006 Mar 15;26(11):2852-61. PMID:16540562 doi:26/11/2852
- ↑ Mollerud S, Pinto A, Marconi L, Frydenvang K, Thorsen TS, Laulumaa S, Venskutonyte R, Winther S, Moral AMC, Tamborini L, Conti P, Pickering DS, Kastrup JS. Structure and Affinity of Two Bicyclic Glutamate Analogues at AMPA and Kainate Receptors. ACS Chem Neurosci. 2017 Sep 20;8(9):2056-2064. doi: 10.1021/acschemneuro.7b00201., Epub 2017 Jul 21. PMID:28691798 doi:http://dx.doi.org/10.1021/acschemneuro.7b00201
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