9dxs
Ligand-binding and transmembrane domains of kainate receptor GluK2 in complex with positive allosteric modulator BPAM-344 and channel blocker Spermine
Structural highlights
FunctionGRIK2_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 PubMedKainate 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
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