5FHN

Crystal structure of the GluA2 ligand-binding domain (S1S2J) in complex with (S)-2-Amino-3-(5-(2-(3-methylbenzyl)-2H-tetrazol-5-yl)-3-hydroxyisoxazol-4-yl)propanoic acid at 1.6 A resolution

Summary for 5FHN

• Entry DOI: 10.2210/pdb5fhn/pdb
• Related: 2P2A
• Descriptor: Glutamate receptor 2,Glutamate receptor 2, SULFATE ION, GLYCEROL, ... (7 entities in total)
• Functional Keywords: ionotropic glutamate receptor glua2, ligand-binding domain, membrane protein
• Biological source: Rattus norvegicus (Norway Rat); More
• Cellular location: Cell membrane ; Multi-pass membrane protein : P19491
• Total number of polymer chains: 1
• Total formula weight: 30024.42

Authors

Frydenvang, K.,Kastrup, J.S. (deposition date: 2015-12-22, release date: 2016-03-02, Last modification date: 2024-10-16)

Primary citation

Wang, S.Y.,Larsen, Y.,Navarrete, C.V.,Jensen, A.A.,Nielsen, B.,Al-Musaed, A.,Frydenvang, K.,Kastrup, J.S.,Pickering, D.S.,Clausen, R.P.
Tweaking Subtype Selectivity and Agonist Efficacy at (S)-2-Amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propionic acid (AMPA) Receptors in a Small Series of BnTetAMPA Analogues.
J.Med.Chem., 59:2244-2254, 2016

PubMed Abstract: A series of analogues of the (S)-2-Amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propionic acid (AMPA) receptor agonist BnTetAMPA (5b) were synthesized and characterized pharmacologically in radioligand binding assays at native and cloned AMPA receptors and functionally by two-electrode voltage clamp electrophysiology at the four homomeric AMPA receptors expressed in Xenopus laevis oocytes. The analogues 6 and 7 exhibit very different pharmacological profiles with binding affinity preference for the subtypes GluA1 and GluA3, respectively. X-ray crystal structures of three ligands (6, 7, and 8) in complex with the agonist binding domain (ABD) of GluA2 show that they induce full domain closure despite their low agonist efficacies. Trp767 in GluA2 ABD could be an important determinant for partial agonism of this compound series at AMPA receptors, since agonist efficacy also correlated with the location of the Trp767 side chain.

PubMed: 26862980
DOI: 10.1021/acs.jmedchem.5b01982

Experimental method

X-RAY DIFFRACTION (1.6 Å)