6b7h: Difference between revisions
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==Structure of mGluR3 with an agonist== | ==Structure of mGluR3 with an agonist== | ||
<StructureSection load='6b7h' size='340' side='right' caption='[[6b7h]], [[Resolution|resolution]] 2.82Å' scene=''> | <StructureSection load='6b7h' size='340' side='right'caption='[[6b7h]], [[Resolution|resolution]] 2.82Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[6b7h]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6B7H OCA]. For a <b>guided tour on the structure components</b> use [http:// | <table><tr><td colspan='2'>[[6b7h]] is a 1 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=6B7H OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6B7H FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=CWY:(1S,2S,4S,5R,6S)-2-amino-4-[(3-methoxybenzene-1-carbonyl)amino]bicyclo[3.1.0]hexane-2,6-dicarboxylic+acid'>CWY</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=CWY:(1S,2S,4S,5R,6S)-2-amino-4-[(3-methoxybenzene-1-carbonyl)amino]bicyclo[3.1.0]hexane-2,6-dicarboxylic+acid'>CWY</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr> | ||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http:// | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">GRM3, GPRC1C, MGLUR3 ([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://proteopedia.org/fgij/fg.htm?mol=6b7h FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6b7h OCA], [http://pdbe.org/6b7h PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6b7h RCSB], [http://www.ebi.ac.uk/pdbsum/6b7h PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6b7h ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Function == | == Function == | ||
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</div> | </div> | ||
<div class="pdbe-citations 6b7h" style="background-color:#fffaf0;"></div> | <div class="pdbe-citations 6b7h" style="background-color:#fffaf0;"></div> | ||
==See Also== | |||
*[[Metabotropic glutamate receptor 3D structures|Metabotropic glutamate receptor 3D structures]] | |||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Human]] | |||
[[Category: Large Structures]] | |||
[[Category: Clawson, D K]] | [[Category: Clawson, D K]] | ||
[[Category: Monn, J A]] | [[Category: Monn, J A]] | ||
[[Category: Membrane protein-agonist complex]] | [[Category: Membrane protein-agonist complex]] | ||
[[Category: Mglur3 glutamate]] | [[Category: Mglur3 glutamate]] | ||
Revision as of 00:37, 29 October 2020
Structure of mGluR3 with an agonistStructure of mGluR3 with an agonist
Structural highlights
Function[GRM3_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. Signaling inhibits adenylate cyclase activity.[1] Publication Abstract from PubMedMultiple therapeutic opportunities have been suggested for compounds capable of selective activation of metabotropic glutamate 3 (mGlu3) receptors, but small molecule tools are lacking. As part of our ongoing efforts to identify potent, selective, and systemically bioavailable agonists for mGlu2 and mGlu3 receptor subtypes, a series of C4beta-N-linked variants of (1 S,2 S,5 R,6 S)-2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid 1 (LY354740) were prepared and evaluated for both mGlu2 and mGlu3 receptor binding affinity and functional cellular responses. From this investigation we identified (1 S,2 S,4 S,5 R,6 S)-2-amino-4-[(3-methoxybenzoyl)amino]bicyclo[3.1.0]hexane-2,6-dicarboxylic acid 8p (LY2794193), a molecule that demonstrates remarkable mGlu3 receptor selectivity. Crystallization of 8p with the amino terminal domain of hmGlu3 revealed critical binding interactions for this ligand with residues adjacent to the glutamate binding site, while pharmacokinetic assessment of 8p combined with its effect in an mGlu2 receptor-dependent behavioral model provides estimates for doses of this compound that would be expected to selectively engage and activate central mGlu3 receptors in vivo. Synthesis and Pharmacological Characterization of C4beta-Amide-Substituted 2-Aminobicyclo[3.1.0]hexane-2,6-dicarboxylates. Identification of (1 S,2 S,4 S,5 R,6 S)-2-Amino-4-[(3-methoxybenzoyl)amino]bicyclo[3.1.0]hexane-2,6-dicarboxylic Acid (LY2794193), a Highly Potent and Selective mGlu3 Receptor Agonist.,Monn JA, Henry SS, Massey SM, Clawson DK, Chen Q, Diseroad BA, Bhardwaj RM, Atwell S, Lu F, Wang J, Russell M, Heinz BA, Wang XS, Carter JH, Getman BG, Adragni K, Broad LM, Sanger HE, Ursu D, Catlow JT, Swanson S, Johnson BG, Shaw DB, McKinzie DL, Hao J J Med Chem. 2018 Mar 22;61(6):2303-2328. doi: 10.1021/acs.jmedchem.7b01481. Epub , 2018 Feb 6. PMID:29350927[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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