| Structural highlights
9dxr is a 4 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: | Electron Microscopy, Resolution 3.1Å |
| Ligands: | , , , , |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
GRIK2_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. Modulates cell surface expression of NETO2 (By similarity).[1] [2]
Publication Abstract from PubMed
Kainate receptors (KARs) are a subtype of ionotropic glutamate receptor (iGluR) channels, a superfamily of ligand-gated ion channels which mediate the majority of excitatory neurotransmission in the central nervous system. KARs modulate neuronal circuits and plasticity during development and are implicated in neurological disorders, including epilepsy, depression, schizophrenia, anxiety, and autism. Calcium-permeable KARs undergo ion channel block, but the therapeutic potential of channel blockers remains underdeveloped, mainly due to limited structural knowledge. Here, we present closed-state structures of GluK2 KAR homotetramers in complex with ion channel blockers NpTx-8, PhTx-74, Kukoamine A, and spermine. We find that blockers reside inside the GluK2 ion channel pore, intracellular to the closed M3 helix bundle-crossing gate, with their hydrophobic heads filling the central cavity and positively charged polyamine tails spanning the selectivity filter. Molecular dynamics (MD) simulations of our structures illuminate interactions responsible for different affinity and binding poses of the blockers. Our structures elucidate the trapping mechanism of KAR channel block and provide a template for designing new blockers that can selectively target calcium-permeable KARs in neuropathologies.
Trapping of spermine, Kukoamine A, and polyamine toxin blockers in GluK2 kainate receptor channels.,Gangwar SP, Yelshanskaya MV, Aktolun M, Yen LY, Newton TP, Stromgaard K, Kurnikova MG, Sobolevsky AI Nat Commun. 2024 Nov 26;15(1):10257. doi: 10.1038/s41467-024-54538-x. PMID:39592599[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Martin S, Nishimune A, Mellor JR, Henley JM. SUMOylation regulates kainate-receptor-mediated synaptic transmission. Nature. 2007 May 17;447(7142):321-5. Epub 2007 May 7. PMID:17486098 doi:nature05736
- ↑ Weston MC, Schuck P, Ghosal A, Rosenmund C, Mayer ML. Conformational restriction blocks glutamate receptor desensitization. Nat Struct Mol Biol. 2006 Dec;13(12):1120-7. Epub 2006 Nov 19. PMID:17115050 doi:http://dx.doi.org/10.1038/nsmb1178
- ↑ Gangwar SP, Yelshanskaya MV, Aktolun M, Yen LY, Newton TP, Strømgaard K, Kurnikova MG, Sobolevsky AI. Trapping of spermine, Kukoamine A, and polyamine toxin blockers in GluK2 kainate receptor channels. Nat Commun. 2024 Nov 26;15(1):10257. PMID:39592599 doi:10.1038/s41467-024-54538-x
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