6FZ4

Structure of GluK1 ligand-binding domain in complex with N-(7-fluoro-2,3-dioxo-6-(trifluoromethyl)-3,4-dihydroquinoxalin-1(2H)-yl)-2-hydroxybenzamide at 1.85 A resolution

Summary for 6FZ4

• Entry DOI: 10.2210/pdb6fz4/pdb
• Descriptor: Glutamate receptor ionotropic, kainate 1,Glutamate receptor ionotropic, kainate 1, GLYCEROL, SULFATE ION, ... (6 entities in total)
• Functional Keywords: kainate receptor ligand-binding domain, gluk1-s1s2, membrane protein
• Biological source: Rattus norvegicus (Rat); More
• Total number of polymer chains: 1
• Total formula weight: 30083.69

Authors

Kastrup, J.S.,Frydenvang, K.,Mollerud, S. (deposition date: 2018-03-14, release date: 2019-01-23, Last modification date: 2024-01-17)

Primary citation

Pallesen, J.,Mollerud, S.,Frydenvang, K.,Pickering, D.S.,Bornholdt, J.,Nielsen, B.,Pasini, D.,Han, L.,Marconi, L.,Kastrup, J.S.,Johansen, T.N.
N1-Substituted Quinoxaline-2,3-diones as Kainate Receptor Antagonists: X-ray Crystallography, Structure-Affinity Relationships, and in Vitro Pharmacology.
Acs Chem Neurosci, 10:1841-1853, 2019

PubMed Abstract: Among the ionotropic glutamate receptors, the physiological role of kainate receptors is less well understood. Although ligands with selectivity toward the kainate receptor subtype GluK1 are available, tool compounds with selectivity at the remaining kainate receptor subtypes are sparse. Here, we have synthesized a series of quinoxaline-2,3-diones with substitutions in the N1-, 6-, and 7-position to investigate the structure-activity relationship (SAR) at GluK1-3 and GluK5. Pharmacological characterization at native and recombinant kainate and AMPA receptors revealed that compound 37 had a GluK3-binding affinity ( K) of 0.142 μM and 8-fold preference for GluK3 over GluK1. Despite lower binding affinity of 22 at GluK3 ( K = 2.91 μM), its preference for GluK3 over GluK1 and GluK2 was >30-fold. Compound 37 was crystallized with the GluK1 ligand-binding domain to understand the SAR. The X-ray structure showed that 37 stabilized the protein in an open conformation, consistent with an antagonist binding mode.

PubMed: 30620174
DOI: 10.1021/acschemneuro.8b00726

Experimental method

X-RAY DIFFRACTION (1.85 Å)