9D5K

Human Adenosine Deaminase Acting on dsRNA (ADAR2-RD) bound to dsRNA containing an expanded cytidine analog at the -1 position of the guide strand

これはPDB形式変換不可エントリーです。

9D5K の概要

• エントリーDOI: 10.2210/pdb9d5k/pdb
• 関連するPDBエントリー: 6VFF 8E0F 8E4X
• 分子名称: Isoform 4 of Double-stranded RNA-specific editase 1, RNA Top Strand, RNA Bottom Strand, ... (7 entities in total)
• 機能のキーワード: adenosine deaminase, dsrna, complex, rna editing, cytidine analog, rna binding protein, rna binding protein-rna complex, rna binding protein/rna
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 129932.92

構造登録者

Fisher, A.J.,Cheng, J.,Manjunath, A.,Campbell, K. (登録日: 2024-08-13, 公開日: 2024-11-06)

主引用文献

Manjunath, A.,Cheng, J.,Campbell, K.B.,Jacobsen, C.S.,Mendoza, H.G.,Bierbaum, L.,Jauregui-Matos, V.,Doherty, E.E.,Fisher, A.J.,Beal, P.A.
Nucleoside Analogs in ADAR Guide Strands Enable Editing at 5'-G A Sites.
Biomolecules, 14:-, 2024

PubMed Abstract: Adenosine Deaminases Acting on RNA (ADARs) are members of a family of RNA editing enzymes that catalyze the conversion of adenosine into inosine in double-stranded RNA (dsRNA). ADARs' selective activity on dsRNA presents the ability to correct mutations at the transcriptome level using guiding oligonucleotides. However, this approach is limited by ADARs' preference for specific sequence contexts to achieve efficient editing. Substrates with a guanosine adjacent to the target adenosine in the 5' direction (5'-GA) are edited less efficiently compared to substrates with any other canonical nucleotides at this position. Previous studies showed that a G/purine mismatch at this position results in more efficient editing than a canonical G/C pair. Herein, we investigate a series of modified oligonucleotides containing purine or size-expanded nucleoside analogs on guide strands opposite the 5'-G (-1 position). The results demonstrate that modified adenosine and inosine analogs enhance editing at 5'-GA sites. Additionally, the inclusion of a size-expanded cytidine analog at this position improves editing over a control guide bearing cytidine. High-resolution crystal structures of ADAR:/RNA substrate complexes reveal the manner by which both inosine and size-expanded cytidine are capable of activating editing at 5'-GA sites. Further modification of these altered guide sequences for metabolic stability in human cells demonstrates that the incorporation of specific purine analogs at the -1 position significantly improves editing at 5'-GA sites.

PubMed: 39456162
DOI: 10.3390/biom14101229

実験手法

X-RAY DIFFRACTION (2.697 Å)