3BBR

Crystal structure of the iGluR2 ligand binding core (S1S2J-N775S) in complex with a dimeric positive modulator as well as glutamate at 2.25 A resolution

Summary for 3BBR

• Entry DOI: 10.2210/pdb3bbr/pdb
• Related: 1LBC 2AL4 2AL5
• Descriptor: Glutamate receptor 2, SULFATE ION, CHLORIDE ION, ... (7 entities in total)
• Functional Keywords: ampa receptor, glur2, s1s2, ligand binding core, point mutation, n775s, dimeric positive modulator, agonist, cell junction, glycoprotein, ion transport, ionic channel, lipoprotein, membrane, palmitate, phosphorylation, postsynaptic cell membrane, rna editing, synapse, transmembrane, transport, membrane protein
• Biological source: Rattus norvegicus (rat); More
• Cellular location: Cell membrane; Multi-pass membrane protein: P19491
• Total number of polymer chains: 2
• Total formula weight: 59808.11

Authors

Kastrup, J.S.,Gajhede, M. (deposition date: 2007-11-11, release date: 2007-12-04, Last modification date: 2024-11-13)

Primary citation

Kaae, B.H.,Harpsoe, K.,Kastrup, J.S.,Sanz, A.C.,Pickering, D.S.,Metzler, B.,Clausen, R.P.,Gajhede, M.,Sauerberg, P.,Liljefors, T.,Madsen, U.
Structural proof of a dimeric positive modulator bridging two identical AMPA receptor-binding sites
Chem.Biol., 14:1294-1303, 2007

PubMed Abstract: Dimeric positive allosteric modulators of ionotropic glutamate receptors were designed, synthesized, and characterized pharmacologically in electrophysiological experiments. The designed compounds are dimers of arylpropylsulfonamides and have been constructed without a linker. The monomeric arylpropylsulfonamides were derived from known modulators and target the cyclothiazide-binding site at the AMPA receptors. The three stereoisomers--R,R, meso, and S,S--of the two constructed dimers were prepared, and in vitro testing showed the R,R forms to be the most potent stereoisomers. The biarylpropylsulfonamides have dramatically increased potencies, more than three orders of magnitude higher than the corresponding monomers. Dimer (R,R)-2a was cocrystallized with the GluR2-S1S2J construct, and an X-ray crystallographic analysis showed (R,R)-2a to bridge two identical binding pockets on two neighboring GluR2 subunits. Thus, this is biostructural evidence of a homomeric dimer bridging two identical receptor-binding sites.

PubMed: 18022568
DOI: 10.1016/j.chembiol.2007.10.012

Experimental method

X-RAY DIFFRACTION (2.25 Å)