5CC2

STRUCTURE OF THE LIGAND-BINDING DOMAIN OF THE IONOTROPIC GLUTAMATE RECEPTOR-LIKE GLUD2 IN COMPLEX WITH 7-CKA

Summary for 5CC2

• Entry DOI: 10.2210/pdb5cc2/pdb
• Related: 2V3T 2V3U
• Descriptor: Glutamate receptor ionotropic, delta-2, 7-Chlorokynurenic acid, GLYCEROL, ... (5 entities in total)
• Functional Keywords: ionotropic glutamate receptor, glud2, ligand binding domain, nmda receptor antagonist, signaling protein
• Biological source: Rattus norvegicus (Rat); More
• Cellular location: Cell membrane ; Multi-pass membrane protein : Q63226
• Total number of polymer chains: 1
• Total formula weight: 30736.06

Authors

Naur, P.,Gajhede, M.,Kastrup, J.S. (deposition date: 2015-07-01, release date: 2015-12-30, Last modification date: 2024-01-10)

Primary citation

Kristensen, A.S.,Hansen, K.B.,Naur, P.,Olsen, L.,Kurtkaya, N.L.,Dravid, S.M.,Kvist, T.,Yi, F.,Phlsgaard, J.,Clausen, R.P.,Gajhede, M.,Kastrup, J.S.,Traynelis, S.F.
Pharmacology and Structural Analysis of Ligand Binding to the Orthosteric Site of Glutamate-Like GluD2 Receptors.
Mol.Pharmacol., 89:253-262, 2016

PubMed Abstract: The GluD2 receptor is a fundamental component of postsynaptic sites in Purkinje neurons, and is required for normal cerebellar function. GluD2 and the closely related GluD1 are classified as members of the ionotropic glutamate receptor (iGluR) superfamily on the basis of sequence similarity, but do not bind l-glutamate. The amino acid neurotransmitter D-Ser is a GluD2 receptor ligand, and endogenous D-Ser signaling through GluD2 has recently been shown to regulate endocytosis of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-type iGluRs during synaptic plasticity in the cerebellum, such as long-term depression. Here, we investigate the pharmacology of the orthosteric binding site in GluD2 by examining the activity of analogs of D-Ser and GluN1 glycine site competitive antagonists at GluD2 receptors containing the lurcher mutation (GluD2(LC)), which promotes spontaneous channel activation. We identify several compounds that modulate GluD2(LC), including a halogenated alanine analog as well as the kynurenic acid analog 7-chloro-4-oxo-1H-quinoline-2-carboxylic acid (7-chlorokynurenic acid; 7-CKA). By correlating thermodynamic and structural data for 7-CKA binding to the isolated GluD2 ligand binding domain (GluD2-LBD), we find that binding 7-CKA to GluD2-LBD differs from D-Ser by inducing an intermediate cleft closure of the clamshell-shaped LBD. The GluD2 ligands identified here can potentially serve as a starting point for development of GluD2-selective ligands useful as tools in studies of the signaling role of the GluD2 receptor in the brain.

PubMed: 26661043
DOI: 10.1124/mol.115.100909

Experimental method

X-RAY DIFFRACTION (2.501 Å)