3PD9

X-ray structure of the ligand-binding core of GluA2 in complex with (R)-5-HPCA at 2.1 A resolution

Summary for 3PD9

• Entry DOI: 10.2210/pdb3pd9/pdb
• Related: 1NNP 3PD8
• Descriptor: Glutamate receptor 2, (5R)-3-hydroxy-4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine-5-carboxylic acid, SULFATE ION, ... (6 entities in total)
• Functional Keywords: ionotropic glutamate receptor glua2, ligand-binding core, agonist complex, membrane protein
• Biological source: Rattus norvegicus (brown rat,rat,rats); More
• Total number of polymer chains: 2
• Total formula weight: 59367.79

Authors

Frydenvang, K.,Kastrup, J.S. (deposition date: 2010-10-22, release date: 2010-12-29, Last modification date: 2024-10-30)

Primary citation

Frydenvang, K.,Pickering, D.S.,Greenwood, J.R.,Krogsgaard-Larsen, N.,Brehm, L.,Nielsen, B.,Vogensen, S.B.,Hald, H.,Kastrup, J.S.,Krogsgaard-Larsen, P.,Clausen, R.P.
Biostructural and pharmacological studies of bicyclic analogues of the 3-isoxazolol glutamate receptor agonist ibotenic acid.
J. Med. Chem., 53:8354-8361, 2010

PubMed Abstract: We describe an improved synthesis and detailed pharmacological characterization of the conformationally restricted analogue of the naturally occurring nonselective glutamate receptor agonist ibotenic acid (RS)-3-hydroxy-4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine-7-carboxylic acid (7-HPCA, 5) at AMPA receptor subtypes. Compound 5 was shown to be a subtype-discriminating agonist at AMPA receptors with higher binding affinity and functional potency at GluA1/2 compared to GluA3/4, unlike the isomeric analogue (RS)-3-hydroxy-4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine-5-carboxylic acid (5-HPCA, 4) that binds to all AMPA receptor subtypes with comparable potency. Biostructural X-ray crystallographic studies of 4 and 5 reveal different binding modes of (R)-4 and (S)-5 in the GluA2 agonist binding domain. WaterMap analysis of the GluA2 and GluA4 binding pockets with (R)-4 and (S)-5 suggests that the energy of hydration sites is ligand dependent, which may explain the observed selectivity.

PubMed: 21067182
DOI: 10.1021/jm101218a

Experimental method

X-RAY DIFFRACTION (2.1 Å)