4xas
From Proteopedia
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| - | '''Unreleased structure''' | ||
| - | + | ==mGluR2 ECD ligand complex== | |
| + | <StructureSection load='4xas' size='340' side='right'caption='[[4xas]], [[Resolution|resolution]] 2.35Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[4xas]] is a 2 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=4XAS OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4XAS FirstGlance]. <br> | ||
| + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.35Å</td></tr> | ||
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=40H:(1R,4S,5S,6S)-4-AMINOSPIRO[BICYCLO[3.1.0]HEXANE-2,1-CYCLOPROPANE]-4,6-DICARBOXYLIC+ACID'>40H</scene></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=4xas FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4xas OCA], [https://pdbe.org/4xas PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4xas RCSB], [https://www.ebi.ac.uk/pdbsum/4xas PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4xas ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Function == | ||
| + | [https://www.uniprot.org/uniprot/GRM2_HUMAN GRM2_HUMAN] G-protein coupled receptor for glutamate. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors, such as adenylate cyclase. Signaling inhibits adenylate cyclase activity. May mediate suppression of neurotransmission or may be involved in synaptogenesis or synaptic stabilization.<ref>PMID:18297054</ref> <ref>PMID:22300836</ref> <ref>PMID:23129762</ref> <ref>PMID:7620613</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | As part of our ongoing research to identify novel agents acting at metabotropic glutamate 2 (mGlu2) and 3 (mGlu3) receptors, we have previously reported the identification of the C4alpha-methyl analog of mGlu2/3 receptor agonist 1 (LY354740). This molecule, 1S,2S,4R,5R,6S-2-amino-4-methylbicyclo[3.1.0]hexane-2,6-dicarboxylate 2 (LY541850), exhibited an unexpected mGlu2 agonist/mGlu3 antagonist pharmacological profile, whereas the C4beta-methyl diastereomer (3) possessed dual mGlu2/3 receptor agonist activity. We have now further explored this structure-activity relationship through the preparation of cyclic and acyclic C4-disubstituted analogs of 1, leading to the identification of C4-spirocyclopropane 5 (LY2934747), a novel, potent, and systemically bioavailable mGlu2/3 receptor agonist which exhibits both antipsychotic and analgesic properties in vivo. In addition, through the combined use of protein-ligand X-ray crystallography employing recombinant human mGlu2/3 receptor amino terminal domains, molecular modeling, and site-directed mutagenesis, a molecular basis for the observed pharmacological profile of compound 2 is proposed. | ||
| - | + | Synthesis and Pharmacological Characterization of C4-Disubstituted Analogs of 1S,2S,5R,6S-2-Aminobicyclo[3.1.0]hexane-2,6-dicarboxylate: Identification of a Potent, Selective Metabotropic Glutamate Receptor Agonist and Determination of Agonist-Bound Human mGlu2 and mGlu3 Amino Terminal Domain Structures.,Monn JA, Prieto L, Taboada L, Pedregal C, Hao J, Reinhard MR, Henry SS, Goldsmith PJ, Beadle CD, Walton L, Man T, Rudyk H, Clark B, Tupper D, Baker SR, Lamas C, Montero C, Marcos A, Blanco J, Bures M, Clawson DK, Atwell S, Lu F, Wang J, Russell M, Heinz BA, Wang X, Carter JH, Xiang C, Catlow JT, Swanson S, Sanger H, Broad LM, Johnson MP, Knopp KL, Simmons RM, Johnson BG, Shaw DB, McKinzie DL J Med Chem. 2015 Feb 5. PMID:25602126<ref>PMID:25602126</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| - | [[Category: Clawson | + | <div class="pdbe-citations 4xas" style="background-color:#fffaf0;"></div> |
| + | |||
| + | ==See Also== | ||
| + | *[[Metabotropic glutamate receptor 3D structures|Metabotropic glutamate receptor 3D structures]] | ||
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Homo sapiens]] | ||
| + | [[Category: Large Structures]] | ||
| + | [[Category: Clawson DK]] | ||
Current revision
mGluR2 ECD ligand complex
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