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5cnk

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Revision as of 07:39, 7 October 2015

mglur3 with glutamate

Structural highlights

5cnk is a 3 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	,
Related:	5cni, 5cnj, 5cnm
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum

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 PubMed

Identification of orthosteric mGlu2/3 receptor agonists capable of discriminating between individual mGlu2 and mGlu3 subtypes has been highly challenging owing to the glutamate-site sequence homology between these proteins. Herein we detail the preparation and characterization of a series of molecules related to 1S,2S,5R,6S-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylate 1 (LY354740) bearing C4-thiotriazole substituents. Based on second messenger responses in cells expressing recombinant human mGlu2/3 subtypes, a number of high potency and efficacy mGlu2 receptor agonists exhibiting low potency mGlu3 partial agonist / antagonist activity were identified. From this, (1R,2S,4R,5R,6R)-2-Amino-4-(1H-1,2,4-triazol-3-ylsulfanyl)bicyclo[3.1.0]hexane-2, 6-dicarboxylic acid 14a (LY2812223) was further characterized. Co-crystallization of 14a with the amino terminal domains of hmGlu2 and hmGlu3 combined with site-directed mutation studies has clarified the underlying molecular basis of this unique pharmacology. Evaluation of 14a in a rat model responsive to mGlu2 receptor activation coupled with a measure of central drug disposition provides evidence that this molecule engages and activates central mGlu2 receptors in vivo.

Synthesis and Pharmacological Characterization of C4-(Thiotriazolyl)-Substituted-2-Aminobicyclo[3.1.0]hexane-2,6-Dicarboxylates. Identification of (1R,2S,4R,5R,6R)-2-Amino-4-(1H-1,2,4-triazol-3-ylsulfanyl)bicyclo[3.1.0]hexane-2, 6-dicarboxylic acid (LY2812223), a Highly Potent, Functionally Selective mGlu2 Receptor Agonist.,Monn JA, Prieto L, Taboada L, Hao J, Reinhard MR, Henry SS, 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, Getman BG, Catlow JT, Swanson S, Johnson BG, Shaw DB, McKinzie DL J Med Chem. 2015 Aug 27. PMID:26313429^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Makoff A, Volpe F, Lelchuk R, Harrington K, Emson P. Molecular characterization and localization of human metabotropic glutamate receptor type 3. Brain Res Mol Brain Res. 1996 Aug;40(1):55-63. PMID:8840013
↑ Monn JA, Prieto L, Taboada L, Hao J, Reinhard MR, Henry SS, 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, Getman BG, Catlow JT, Swanson S, Johnson BG, Shaw DB, McKinzie DL. Synthesis and Pharmacological Characterization of C4-(Thiotriazolyl)-Substituted-2-Aminobicyclo[3.1.0]hexane-2,6-Dicarboxylates. Identification of (1R,2S,4R,5R,6R)-2-Amino-4-(1H-1,2,4-triazol-3-ylsulfanyl)bicyclo[3.1.0]hexane-2, 6-dicarboxylic acid (LY2812223), a Highly Potent, Functionally Selective mGlu2 Receptor Agonist. J Med Chem. 2015 Aug 27. PMID:26313429 doi:http://dx.doi.org/10.1021/acs.jmedchem.5b01124

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5cnk"

Categories: Clawson, D K | Monn, J A | Glutamate receptor | Signaling protein

@@ Line 5: / Line 5: @@
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GGL:GAMMA-L-GLUTAMIC+ACID'>GGL</scene>, <scene name='pdbligand=IOD:IODIDE+ION'>IOD</scene></td></tr>
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5cni|5cni]], [[5cnj|5cnj]], [[5cnm|5cnm]]</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=5cnk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5cnk OCA], [http://www.rcsb.org/pdb/explore.do?structureId=5cnk RCSB], [http://www.ebi.ac.uk/pdbsum/5cnk PDBsum]</span></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=5cnk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5cnk OCA], [http://pdbe.org/5cnk PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5cnk RCSB], [http://www.ebi.ac.uk/pdbsum/5cnk PDBsum]</span></td></tr>
 </table>
 == Function ==
@@ Line 17: / Line 17: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 5cnk" style="background-color:#fffaf0;"></div>
 == References ==
 <references/>

5cnk

From Proteopedia

Revision as of 07:39, 7 October 2015

mglur3 with glutamate

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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