2WKY

Crystal structure of the ligand-binding core of GluR5 in complex with the agonist 4-AHCP

Summary for 2WKY

• Entry DOI: 10.2210/pdb2wky/pdb
• Related: 1TXF 1YCJ 2F34 2F35 2F36
• Descriptor: GLUTAMATE RECEPTOR, IONOTROPIC KAINATE 1, CHLORIDE ION, 3-(3-HYDROXY-7,8-DIHYDRO-6H-CYCLOHEPTA[D]ISOXAZOL-4-YL)-L-ALANINE, ... (4 entities in total)
• Functional Keywords: membrane protein, synapse, membrane, receptor, transport, ion channel, rna editing, glycoprotein, cell junction, ionotropic glutamate receptor, alternative splicing, postsynaptic cell membrane, ionic channel, cell membrane, ion transport, transmembrane, phosphoprotein, ligand-binding core
• Biological source: RATTUS NORVEGICUS (RAT)
• Cellular location: Cell membrane; Multi-pass membrane protein: P22756
• Total number of polymer chains: 2
• Total formula weight: 59022.52

Authors

Naur, P.,Gajhede, M.,Kastrup, J.S. (deposition date: 2009-06-18, release date: 2009-07-21, Last modification date: 2024-10-23)

Primary citation

Clausen, R.P.,Naur, P.,Kristensen, A.S.,Greenwood, J.R.,Strange, M.,Brauner-Osborne, H.,Jensen, A.A.,Nielsen, A.S.,Geneser, U.,Ringgaard, L.M.,Nielsen, B.,Pickering, D.S.,Brehm, L.,Gajhede, M.,Krogsgaard-Larsen, P.,Kastrup, J.S.
The Glutamate Receptor Glur5 Agonist (S)-2-Amino-3-(3-Hydroxy-7,8-Dihydro-6H-Cyclohepta[D]Isoxazol-4-Yl)Propionic Acid and the 8-Methyl Analogue: Synthesis, Molecular Pharmacology, and Biostructural Characterization
J.Med.Chem., 52:4911-, 2009

PubMed Abstract: The design, synthesis, and pharmacological characterization of a highly potent and selective glutamate GluR5 agonist is reported. (S)-2-Amino-3-((RS)-3-hydroxy-8-methyl-7,8-dihydro-6H-cyclohepta[d]isoxazol-4-yl)propionic acid (5) is the 8-methyl analogue of (S)-2-amino-3-(3-hydroxy-7,8-dihydro-6H-cyclohepta[d]isoxazol-4-yl)propionic acid ((S)-4-AHCP, 4). Compound 5 displays an improved selectivity profile compared to 4. A versatile stereoselective synthetic route for this class of compounds is presented along with the characterization of the binding affinity of 5 to ionotropic glutamate receptors (iGluRs). Functional characterization of 5 at cloned iGluRs using a calcium imaging assay and voltage-clamp recordings show a different activation of GluR5 compared to (S)-glutamic acid (Glu), kainic acid (KA, 1), and (S)-2-amino-3-(3-hydroxy-5-tert-butyl-4-isoxazolyl)propionic acid ((S)-ATPA, 3) as previously demonstrated for 4. An X-ray crystallographic analysis of 4 and computational analyses of 4 and 5 bound to the GluR5 agonist binding domain (ABD) are presented, including a watermap analysis, which suggests that water molecules in the agonist binding site are important selectivity determinants.

PubMed: 19588945
DOI: 10.1021/JM900565C

Experimental method

X-RAY DIFFRACTION (2.2 Å)