4XAQ

mGluR2 ECD and mGluR3 ECD with ligands

Summary for 4XAQ

• Entry DOI: 10.2210/pdb4xaq/pdb
• Related: 4XAR 4XAS
• Descriptor: Metabotropic glutamate receptor 2, (1S,2S,5R,6S)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid, SULFATE ION, ... (5 entities in total)
• Functional Keywords: mglur2 mglur3, signaling protein
• Biological source: Homo sapiens (Human)
• Cellular location: Cell membrane; Multi-pass membrane protein: Q14416
• Total number of polymer chains: 2
• Total formula weight: 112094.50

Authors

Clawson, D.K. (deposition date: 2014-12-15, release date: 2015-02-04, Last modification date: 2024-10-16)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.21 Å)