| Structural highlights
4qf9 is a 3 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | 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
Two alpha-amino acid-functionalized quinoxalines, 1a (CNG-10301) and 1b (CNG-10300), of a quinoxaline moiety coupled to an amino acid moiety were designed, synthesized, and characterized pharmacologically. While 1a displayed low affinity at native AMPA, KA, and NMDA receptors, and at homomeric GluK1,3 receptors, the affinity for GluK2 was in the midmicromolar range (Ki = 136 muM), 1b displayed low to midmicromolar range binding affinity at all the iGluRs (Ki = 9-126 muM). In functional experiments (outside-out patches excised from transfected HEK293T cells), 100 muM 1a partially blocked GluK1 (33% peak response), while GluK2 was unaffected (96% peak response). Furthermore, 1a was shown not to be an agonist at GluK1 and GluK2 at 100 muM. On the other hand, 100 muM 1b fully antagonized GluK1 (8% peak response) but only partially blocked GluK2 (33% peak response). An X-ray structure at 2.3 A resolution of 1b in the GluK1-LBD (ligand-binding domain) disclosed an unexpected binding mode compared to the predictions made during the design phase; the quinoxaline moiety remains to act as an amino acid bioisostere, but the amino acid moiety is oriented into a new area within the GluK1 receptor. The structure of the GluK1-LBD with 1b showed a large variation in domain openings of the three molecules from 25 degrees to 49 degrees , demonstrating that the GluK1-LBD is capable of undergoing major domain movements.
Binding Mode of an alpha-Amino Acid-Linked Quinoxaline-2,3-dione Analogue at Glutamate Receptor Subtype GluK1.,Demmer CS, Moller C, Brown PM, Han L, Pickering DS, Nielsen B, Bowie D, Frydenvang K, Kastrup JS, Bunch L ACS Chem Neurosci. 2015 Apr 9. PMID:25856736[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
- ↑ Demmer CS, Moller C, Brown PM, Han L, Pickering DS, Nielsen B, Bowie D, Frydenvang K, Kastrup JS, Bunch L. Binding Mode of an alpha-Amino Acid-Linked Quinoxaline-2,3-dione Analogue at Glutamate Receptor Subtype GluK1. ACS Chem Neurosci. 2015 Apr 9. PMID:25856736 doi:http://dx.doi.org/10.1021/acschemneuro.5b00038
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