9e9e

Structure of AMPA receptor GluA2 and auxiliary subunit TARP gamma-2 (LBD-TMD) in complex with anti-miR 17 oligonucleotide RGLS4326

spinqualitylabelsall models 9e9e, resolution 3.24Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9e9e 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 3.24Å Ligands: A1BX3 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. CCG2_RAT Regulates the trafficking and gating properties of AMPA-selective glutamate receptors (AMPARs). Promotes their targeting to the cell membrane and synapses and modulates their gating properties by slowing their rates of activation, deactivation and desensitization. Does not show subunit-specific AMPA receptor regulation and regulates all AMPAR subunits. Thought to stabilize the calcium channel in an inactivated (closed) state. Publication Abstract from PubMed Designing safe and effective oligonucleotide (ON) therapeutics requires thorough understanding of structural-activity relationship (SAR) with the intended on-target(s) as well as the unintended off-target(s). Despite encouraging pharmacodynamic activity in a Phase 1b study, development of the first-generation anti-miR-17 ON RGLS4326 for the treatment of autosomal dominant polycystic kidney disease was discontinued due to dose-limiting central nervous system (CNS)-related toxicity observed in nonclinical chronic toxicity studies. Here, we provide SAR evidence that the nucleobase guanine at the 3'-terminus of RGLS4326 drives an unexpected off-target aptamer-like direct interaction with alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), thereby causing CNS toxicity. By replacing the 3'-terminal guanine with adenine, we discover the next-generation anti-miR-17 RGLS8429 that is devoid of off-target AMPAR interaction and CNS toxicity while preserving the potency against the on-target miR-17. Here, we show a way to avoid off-target CNS effects and, more importantly, data that support the clinical development of RGLS8429. The nucleobase guanine at the 3'-terminus of oligonucleotide RGLS4326 drives off-target AMPAR inhibition and CNS toxicity.,Valencia T, Yen LY, Berman C, Vincent T, Davis S, Varrone F, Huang J, Mastroianni J, Carlson M, Owen T, Kamel A, Drygin D, Kinberger GA, Gangwar SP, Yelshanskaya MV, Ridley J, Kirby R, Alvarez J, Lakhia R, Patel V, Sobolevsky AI, Lee EC Nat Commun. 2025 Nov 28;16(1):10762. doi: 10.1038/s41467-025-65799-5. PMID:41315228 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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