9E9E

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

これはPDB形式変換不可エントリーです。

9E9E の概要

• エントリーDOI: 10.2210/pdb9e9e/pdb
• EMDBエントリー: 47793
• 分子名称: Isoform Flip of Glutamate receptor 2,Voltage-dependent calcium channel gamma-2 subunit, O-{[(1S,3S,4R,6S,7R)-7-{[(R)-{[(1R,3R,4R,6S,7R)-3-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)-7-hydroxy-6-methyl-2,5-dioxabicyclo[2.2.1]heptan-1-yl]methoxy}(sulfanyl)phosphoryl]oxy}-3-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-6-methyl-2,5-dioxabicyclo[2.2.1]heptan-1-yl]methyl} O-[(2R,3S,4R,5S)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-methoxy-2-methyloxolan-3-yl] hydrogen (R)-phosphorothioate (2 entities in total)
• 機能のキーワード: ampa receptor, tarp gamma-2, ion channel, anti-mir 17, oligonucleotide, signaling protein
• 由来する生物種: Rattus norvegicus (Norway rat); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 463596.41

構造登録者

Yen, L.Y.,Gangwar, S.P.,Yelshanskaya, M.V.,Sobolevsky, A.I. (登録日: 2024-11-08, 公開日: 2026-02-11)

主引用文献

Valencia, T.,Yen, L.Y.,Berman, C.,Vincent, T.,Davis, S.,Varrone, F.,Huang, J.,Mastroianni, J.,Carlson, M.,Owen, T.,Kamel, A.,Drygin, D.,Kinberger, G.A.,Gangwar, S.P.,Yelshanskaya, M.V.,Ridley, J.,Kirby, R.,Alvarez, J.,Lakhia, R.,Patel, V.,Sobolevsky, A.I.,Lee, E.C.
The nucleobase guanine at the 3'-terminus of oligonucleotide RGLS4326 drives off-target AMPAR inhibition and CNS toxicity.
Nat Commun, 16:10762-10762, 2025

PubMed Abstract: 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 α-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.

PubMed: 41315228
DOI: 10.1038/s41467-025-65799-5

実験手法

ELECTRON MICROSCOPY (3.24 Å)