4XAR

mGluR2 ECD and mGluR3 ECD complex with ligands

4XAR の概要

• エントリーDOI: 10.2210/pdb4xar/pdb
• 関連するPDBエントリー: 4XAQ 4XAS
• 分子名称: Metabotropic glutamate receptor 3, (1S,2S,5R,6S)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid, IODIDE ION, ... (4 entities in total)
• 機能のキーワード: mglur2 mglur3 ecd, signaling protein
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Cell membrane ; Multi-pass membrane protein : Q14832
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 59976.97

構造登録者

Clawson, D.K. (登録日: 2014-12-15, 公開日: 2015-02-11, 最終更新日: 2024-10-09)

主引用文献

Monn, J.A.,Prieto, L.,Taboada, L.,Pedregal, C.,Hao, J.,Reinhard, M.R.,Henry, S.S.,Goldsmith, P.J.,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.,Xiang, C.,Catlow, J.T.,Swanson, S.,Sanger, H.,Broad, L.M.,Johnson, M.P.,Knopp, K.L.,Simmons, R.M.,Johnson, B.G.,Shaw, D.B.,McKinzie, D.L.
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.
J.Med.Chem., 58:1776-1794, 2015

PubMed Abstract: 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 C4α-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 C4β-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.

PubMed: 25602126
DOI: 10.1021/jm501612y

実験手法

X-RAY DIFFRACTION (2.26 Å)