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6sbt

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Structure of GluK1 ligand-binding domain (S1S2) in complex with N-(7-(1H-imidazol-1-yl)-2,3-dioxo-6-(trifluoromethyl)-3,4-dihydroquinoxalin-1(2H)-yl benzamide at 2.3 A resolution

Structural highlights

6sbt is a 1 chain structure with sequence from Rattus norvegicus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.3Å
Ligands:	, , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

GRIK1_RAT Ionotropic glutamate receptor. L-glutamate acts as an excitatory neurotransmitter at many synapses in the central nervous system. Binding of the excitatory neurotransmitter L-glutamate induces a conformation change, leading to the opening of the cation channel, and thereby converts the chemical signal to an electrical impulse. The receptor then desensitizes rapidly and enters a transient inactive state, characterized by the presence of bound agonist. May be involved in the transmission of light information from the retina to the hypothalamus.^[1]

Publication Abstract from PubMed

Selective pharmacological tool compounds are invaluable for understanding the functions of the various ionotropic glutamate receptor subtypes. For the kainate receptors these compounds are few. Here we have synthesized 9 novel quinoxaline-2,3-diones with substitutions in the 7-position to investigate the structure-activity relationship at kainate and AMPA receptors. Compound 11 exhibited the highest binding affinity across GluK1-3 while having a 73-fold selectivity towards kainate vs. AMPA receptors. 11 potently inhibited glutamate evoked currents at homomeric GluK1 and GluK3 receptors in HEK293 cells with Kb values of 65 and 39 nM, respectively. The binding mode of 11 in the ligand binding domain of GluK1 was investigated by X-ray crystallography, revealing that 11 stabilizes the receptor in an open conformation, consistent with its demonstrated antagonism. Furthermore, 11 was tested for analgesic effects in the mouse tail flick test where it significantly increased tail flick latency at doses where NBQX was ineffective.

N-(7-(1H-imidazol-1-yl)-2,3-dioxo-6-(trifluoromethyl)-3,4-dihydroquinoxalin-1(2H) -yl)benzamide - a new kainate receptor selective antagonist and analgesic: Synthesis, X-ray crystallography, structure-affinity relationships, in vitro and in vivo pharmacology.,M Oslash Llerud S, Hansen RB, Pallesen JS, Temperini P, Pasini D, Bornholdt J, Nielsen B, Mamedova E, Chalupnik P, Paternain AV, Lerma J, Del Castillo MD, Andreasen JT, Frydenvang K, Kastrup JS, Johansen TN, Pickering DS ACS Chem Neurosci. 2019 Oct 17. doi: 10.1021/acschemneuro.9b00479. PMID:31622082^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Mayer ML, Ghosal A, Dolman NP, Jane DE. Crystal structures of the kainate receptor GluR5 ligand binding core dimer with novel GluR5-selective antagonists. J Neurosci. 2006 Mar 15;26(11):2852-61. PMID:16540562 doi:26/11/2852
↑ M Oslash Llerud S, Hansen RB, Pallesen JS, Temperini P, Pasini D, Bornholdt J, Nielsen B, Mamedova E, Chalupnik P, Paternain AV, Lerma J, Del Castillo MD, Andreasen JT, Frydenvang K, Kastrup JS, Johansen TN, Pickering DS. N-(7-(1H-imidazol-1-yl)-2,3-dioxo-6-(trifluoromethyl)-3,4-dihydroquinoxalin-1(2H) -yl)benzamide - a new kainate receptor selective antagonist and analgesic: Synthesis, X-ray crystallography, structure-affinity relationships, in vitro and in vivo pharmacology. ACS Chem Neurosci. 2019 Oct 17. doi: 10.1021/acschemneuro.9b00479. PMID:31622082 doi:http://dx.doi.org/10.1021/acschemneuro.9b00479