8ssa

Structure of AMPA receptor GluA2 complex with auxiliary subunits TARP gamma-5 and cornichon-2 bound to glutamate and channel blocker spermidine (desensitized state)

spinqualitylabelsall models 8ssa, resolution 3.88Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8ssa is a 6 chain structure with sequence from Homo sapiens and Rattus norvegicus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 3.88Å Ligands: GLU, PCW, SPD Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function GRIA2_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. 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. In the presence of CACNG4 or CACNG7 or CACNG8, shows resensitization which is characterized by a delayed accumulation of current flux upon continued application of glutamate. CCG5_RAT Regulates the gating properties of AMPA-selective glutamate receptors (AMPARs). Modulates their gating properties by accelerating their rates of activation, deactivation and desensitization. Displays subunit-specific AMPA receptor regulation. Shows specificity for GRIA1, GRIA4 and the long isoform of GRIA2. According to PubMed:18817736, shows only specificity for GRIA2 and specifically to the form of GRIA2 for which a single amino acid in the pore region has been edited from a glutamine to an arginine residue. Thought to stabilize the calcium channel in an inactivated (closed) state. Publication Abstract from PubMed Synaptic complexes of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors (AMPARs) with auxiliary subunits mediate most excitatory neurotransmission and can be targeted to treat neuropsychiatric and neurological disorders, including epilepsy. Here we present cryogenic-electron microscopy structures of rat GluA2 AMPAR complexes with inhibitory mouse gamma5 and potentiating human cornichon-2 (CNIH2) auxiliary subunits. CNIH2 appears to destabilize the desensitized state of the complex by reducing the separation of the upper lobes in ligand-binding domain dimers. At the same time, CNIH2 stabilizes binding of polyamine spermidine to the selectivity filter of the closed ion channel. Nevertheless, CNIH2, and to a lesser extent gamma5, attenuate polyamine block of the open channel and reduce the potency of the antiepileptic drug perampanel that inhibits the synaptic complex allosterically by binding to sites in the ion channel extracellular collar. These findings illustrate the fine-tuning of synaptic complex structure and function in an auxiliary subunit-dependent manner, which is critical for the study of brain region-specific neurotransmission and design of therapeutics for disease treatment. Modulation of GluA2-gamma5 synaptic complex desensitization, polyamine block and antiepileptic perampanel inhibition by auxiliary subunit cornichon-2.,Gangwar SP, Yen LY, Yelshanskaya MV, Korman A, Jones DR, Sobolevsky AI Nat Struct Mol Biol. 2023 Oct;30(10):1481-1494. doi: 10.1038/s41594-023-01080-x. , Epub 2023 Aug 31. PMID:37653241 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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