4YMA

Structure of the ligand-binding domain of GluA2 in complex with the antagonist CNG10109

Summary for 4YMA

• Entry DOI: 10.2210/pdb4yma/pdb
• Related: 1FW0
• Descriptor: Glutamate receptor 2, SULFATE ION, GLYCEROL, ... (7 entities in total)
• Functional Keywords: ionotropic glutamate receptor, ampa receptor glua2, ligand-binding domain, antagonist, signaling protein
• Biological source: Rattus norvegicus (Rat); More
• Cellular location: Cell membrane ; Multi-pass membrane protein : P19491
• Total number of polymer chains: 2
• Total formula weight: 60003.68

Authors

Moller, C.,Tapken, D.,Kastrup, J.S.,Frydenvang, K. (deposition date: 2015-03-06, release date: 2015-08-05, Last modification date: 2024-10-23)

Primary citation

Krogsgaard-Larsen, N.,Storgaard, M.,Moller, C.,Demmer, C.S.,Hansen, J.,Han, L.,Monrad, R.N.,Nielsen, B.,Tapken, D.,Pickering, D.S.,Kastrup, J.S.,Frydenvang, K.,Bunch, L.
Structure-Activity Relationship Study of Ionotropic Glutamate Receptor Antagonist (2S,3R)-3-(3-Carboxyphenyl)pyrrolidine-2-carboxylic Acid.
J.Med.Chem., 58:6131-6150, 2015

PubMed Abstract: Herein we describe the first structure-activity relationship study of the broad-range iGluR antagonist (2S,3R)-3-(3-carboxyphenyl)pyrrolidine-2-carboxylic acid (1) by exploring the pharmacological effect of substituents in the 4, 4', or 5' positions and the bioisosteric substitution of the distal carboxylic acid for a phosphonic acid moiety. Of particular interest is a hydroxyl group in the 4' position 2a which induced a preference in binding affinity for homomeric GluK3 over GluK1 (Ki = 0.87 and 4.8 μM, respectively). Two X-ray structures of ligand binding domains were obtained: 2e in GluA2-LBD and 2f in GluK1-LBD, both at 1.9 Å resolution. Compound 2e induces a D1-D2 domain opening in GluA2-LBD of 17.3-18.8° and 2f a domain opening in GluK1-LBD of 17.0-17.5° relative to the structures with glutamate. The pyrrolidine-2-carboxylate moiety of 2e and 2f shows a similar binding mode as kainate. The 3-carboxyphenyl ring of 2e and 2f forms contacts comparable to those of the distal carboxylate in kainate.

PubMed: 26200741
DOI: 10.1021/acs.jmedchem.5b00750

Experimental method

X-RAY DIFFRACTION (1.895 Å)