4IY6

Crystal structure of the GLUA2 ligand-binding domain (S1S2J-L483Y-N754S) in complex with glutamate and ME-CX516 at 1.72 A resolution

Summary for 4IY6

• Entry DOI: 10.2210/pdb4iy6/pdb
• Related: 2AL4 2AL5 3TDJ 3TDK 4IY5
• Descriptor: Glutamate receptor 2, [(3R)-3-methylpiperidin-1-yl](quinoxalin-6-yl)methanone, [(3S)-3-methylpiperidin-1-yl](quinoxalin-6-yl)methanone, ... (7 entities in total)
• Functional Keywords: ampa receptor ligand-binding domain, glua2 s1s2j-l483y-n754s, me-cx516, allosteric modulation, membrane protein
• Biological source: Rattus norvegicus (rat, brown rat, rats); More
• Cellular location: Cell membrane; Multi-pass membrane protein: P19491
• Total number of polymer chains: 1
• Total formula weight: 30441.97

Authors

Krintel, C.,Frydenvang, K.,Harpsoe, K.,Gajhede, M.,Kastrup, J.S. (deposition date: 2013-01-28, release date: 2013-10-09, Last modification date: 2024-10-16)

Primary citation

Krintel, C.,Harpse, K.,Zachariassen, L.G.,Peters, D.,Frydenvang, K.,Pickering, D.S.,Gajhede, M.,Kastrup, J.S.
Structural analysis of the positive AMPA receptor modulators CX516 and Me-CX516 in complex with the GluA2 ligand-binding domain
Acta Crystallogr.,Sect.D, 69:1645-1652, 2013

PubMed Abstract: Positive allosteric modulators of the ionotropic glutamate receptor A2 (GluA2) can serve as lead compounds for the development of cognitive enhancers. Several benzamide-type (S)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) receptor modulators such as aniracetam, CX516 and CX614 have been shown to inhibit the deactivation of AMPA receptors with a less pronounced effect on desensitization. Despite CX516 being an extensively investigated AMPA receptor modulator and one of the few clinically evaluated compounds, the binding mode of CX516 to AMPA receptors has not been reported. Here, the structures of a GluA2 ligand-binding domain mutant in complex with CX516 and the 3-methylpiperidine analogue of CX516 (Me-CX516) are reported. The structures show that the binding modes of CX516 and Me-CX516 are similar to those of aniracetam and CX614 and that there is limited space for substitution at the piperidine ring of CX516. The results therefore support that CX516, like aniracetam and CX614, modulates deactivation of AMPA receptors.

PubMed: 23999288
DOI: 10.1107/S0907444913011839

Experimental method

X-RAY DIFFRACTION (1.72 Å)