5M2V

Structure of GluK1 ligand-binding domain (S1S2) in complex with (2S,4R)-4-(2-carboxyphenoxy)pyrrolidine-2-carboxylic acid at 3.18 A resolution

Summary for 5M2V

• Entry DOI: 10.2210/pdb5m2v/pdb
• Descriptor: Glutamate receptor ionotropic, kainate 1,Glutamate receptor ionotropic, kainate 1, (2~{S},4~{R})-4-(2-carboxyphenoxy)pyrrolidine-2-carboxylic acid, SULFATE ION, ... (4 entities in total)
• Functional Keywords: kainate receptor ligand-binding domain, gluk1-lbd, gluk1-s1s2, antagonist, membrane protein
• Biological source: Rattus norvegicus (Norway Rat); More
• Cellular location: Cell membrane; Multi-pass membrane protein: P22756
• Total number of polymer chains: 2
• Total formula weight: 59366.66

Authors

Frydenvang, K.,Kastrup, J.S.,Kristensen, C.M. (deposition date: 2016-10-13, release date: 2017-01-11, Last modification date: 2024-10-23)

Primary citation

Krogsgaard-Larsen, N.,Delgar, C.G.,Koch, K.,Brown, P.M.,Moller, C.,Han, L.,Huynh, T.H.,Hansen, S.W.,Nielsen, B.,Bowie, D.,Pickering, D.S.,Kastrup, J.S.,Frydenvang, K.,Bunch, L.
Design and Synthesis of a Series of l-trans-4-Substituted Prolines as Selective Antagonists for the Ionotropic Glutamate Receptors Including Functional and X-ray Crystallographic Studies of New Subtype Selective Kainic Acid Receptor Subtype 1 (GluK1) Antagonist (2S,4R)-4-(2-Carboxyphenoxy)pyrrolidine-2-carboxylic Acid.
J. Med. Chem., 60:441-457, 2017

PubMed Abstract: Ionotropic glutamate receptor antagonists are valuable tool compounds for studies of neurological pathways in the central nervous system. On the basis of rational ligand design, a new class of selective antagonists, represented by (2S,4R)-4-(2-carboxyphenoxy)pyrrolidine-2-carboxylic acid (1b), for cloned homomeric kainic acid receptors subtype 1 (GluK1) was attained (K = 4 μM). In a functional assay, 1b displayed full antagonist activity with IC = 6 ± 2 μM. A crystal structure was obtained of 1b when bound in the ligand binding domain of GluK1. A domain opening of 13-14° was seen compared to the structure with glutamate, consistent with 1b being an antagonist. A structure-activity relationship study showed that the chemical nature of the tethering atom (C, O, or S) linking the pyrrolidine ring and the phenyl ring plays a key role in the receptor selectivity profile and that substituents on the phenyl ring are well accommodated by the GluK1 receptor.

PubMed: 28005385
DOI: 10.1021/acs.jmedchem.6b01516

Experimental method

X-RAY DIFFRACTION (3.18 Å)