5CNI

mGlu2 with Glutamate

5CNI の概要

• エントリーDOI: 10.2210/pdb5cni/pdb
• 関連するPDBエントリー: 5CNJ
• 分子名称: Metabotropic glutamate receptor 2, GLUTAMIC ACID, CHLORIDE ION, ... (6 entities in total)
• 機能のキーワード: receptor, glutamate, metabotropic, signaling protein
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 112721.64

構造登録者

Clawson, D.K.,Atwell, S.,Monn, J.A. (登録日: 2015-07-17, 公開日: 2015-09-09, 最終更新日: 2024-11-06)

主引用文献

Monn, J.A.,Prieto, L.,Taboada, L.,Hao, J.,Reinhard, M.R.,Henry, S.S.,Beadle, C.D.,Walton, L.,Man, T.,Rudyk, H.,Clark, B.,Tupper, D.,Baker, S.R.,Lamas, C.,Montero, C.,Marcos, A.,Blanco, J.,Bures, M.,Clawson, D.K.,Atwell, S.,Lu, F.,Wang, J.,Russell, M.,Heinz, B.A.,Wang, X.,Carter, J.H.,Getman, B.G.,Catlow, J.T.,Swanson, S.,Johnson, B.G.,Shaw, D.B.,McKinzie, D.L.
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., 58:7526-7548, 2015

PubMed Abstract: Identification of orthosteric mGlu(2/3) 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. On the basis of second messenger responses in cells expressing other 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. Cocrystallization 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.

PubMed: 26313429
DOI: 10.1021/acs.jmedchem.5b01124

実験手法

X-RAY DIFFRACTION (2.69 Å)