Structural highlights
Function
[GRIK3_RAT] Receptor for glutamate that functions as ligand-gated ion channel in the central nervous system and plays an important role in excitatory synaptic transmission. L-glutamate acts as an excitatory neurotransmitter at many synapses in the central nervous system. The postsynaptic actions of Glu are mediated by a variety of receptors that are named according to their selective agonists. This receptor binds domoate > kainate >> L-glutamate = quisqualate >> AMPA = NMDA.[1]
Publication Abstract from PubMed
The kainate receptors are the least studied subfamily of ionotropic glutamate receptors. These receptors are thought to have a neuromodulatory role and have been associated with a variety of disorders in the central nervous system. This makes kainate receptors interesting potential drug targets. Today, structures of the ligand binding domain (LBD) of the kainate receptor GluK3 are only known in complex with the endogenous agonist glutamate, the natural product kainate, and two synthetic agonists. Herein we report structures of GluK3 LBD in complex with two 2,4-syn-functionalized (S)-glutamate analogues to investigate their structural potential as chemical scaffolds. Similar binding affinities at GluK3 were determined for the 2-(methylcarbamoyl)ethyl analogue (Ki =4.0 muM) and the 2-(methoxycarbonyl)ethyl analogue (Ki =1.7 muM), in agreement with the similar positioning of the compounds within the binding pocket. As the binding affinity is similar to that of glutamate, this type of Cgamma substituent could be used as a scaffold for introduction of even larger substituents reaching into unexplored binding site regions to achieve subtype selectivity.
Molecular Recognition of Two 2,4-syn-Functionalized (S)-Glutamate Analogues by the Kainate Receptor GluK3 Ligand Binding Domain.,Venskutonyte R, Larsen AP, Frydenvang K, Gajhede M, Sagot E, Assaf Z, Gefflaut T, Pickering DS, Bunch L, Kastrup JS ChemMedChem. 2014 Jul 8. doi: 10.1002/cmdc.201402204. PMID:25044437[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Venskutonyte R, Frydenvang K, Gajhede M, Bunch L, Pickering DS, Kastrup JS. Binding site and interlobe interactions of the ionotropic glutamate receptor GluK3 ligand binding domain revealed by high resolution crystal structure in complex with (S)-glutamate. J Struct Biol. 2011 Sep 1. PMID:21907808 doi:10.1016/j.jsb.2011.08.014
- ↑ Venskutonyte R, Larsen AP, Frydenvang K, Gajhede M, Sagot E, Assaf Z, Gefflaut T, Pickering DS, Bunch L, Kastrup JS. Molecular Recognition of Two 2,4-syn-Functionalized (S)-Glutamate Analogues by the Kainate Receptor GluK3 Ligand Binding Domain. ChemMedChem. 2014 Jul 8. doi: 10.1002/cmdc.201402204. PMID:25044437 doi:http://dx.doi.org/10.1002/cmdc.201402204
