8E4X

Human Adenosine Deaminase Acting on dsRNA (ADAR2-R2D) bound to dsRNA containing a G:3-deaza dA pair adjacent to the target site

8E4X の概要

• エントリーDOI: 10.2210/pdb8e4x/pdb
• 関連するPDBエントリー: 8e0f
• 分子名称: Double-stranded RNA-specific editase 1, RNA (5-R(*GP*CP*UP*CP*GP*CP*GP*AP*UP*GP*CP*GP*(8AZ)P*GP*AP*GP*GP*GP*CP* UP*CP*UP*GP*AP*UP*AP*GP*CP*UP*AP*CP*G)-3), RNA(5-R(*CP*GP*UP*AP*GP*CP*UP*AP*UP*CP*AP*GP*AP*GP*CP*CP*CP*CP*CP*CP*(4DU)*GP*CP*AP*UP*CP*GP*CP*GP*AP*GP*C)-3), ... (6 entities in total)
• 機能のキーワード: protein-rna complex, rna editing, 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: 129981.67

構造登録者

Fisher, A.J.,Mendoza, H.G. (登録日: 2022-08-19, 公開日: 2022-10-26, 最終更新日: 2023-10-18)

主引用文献

Doherty, E.E.,Karki, A.,Wilcox, X.E.,Mendoza, H.G.,Manjunath, A.,Matos, V.J.,Fisher, A.J.,Beal, P.A.
ADAR activation by inducing a syn conformation at guanosine adjacent to an editing site.
Nucleic Acids Res., 50:10857-10868, 2022

PubMed Abstract: ADARs (adenosine deaminases acting on RNA) can be directed to sites in the transcriptome by complementary guide strands allowing for the correction of disease-causing mutations at the RNA level. However, ADARs show bias against editing adenosines with a guanosine 5' nearest neighbor (5'-GA sites), limiting the scope of this approach. Earlier studies suggested this effect arises from a clash in the RNA minor groove involving the 2-amino group of the guanosine adjacent to an editing site. Here we show that nucleosides capable of pairing with guanosine in a syn conformation enhance editing for 5'-GA sites. We describe the crystal structure of a fragment of human ADAR2 bound to RNA bearing a G:G pair adjacent to an editing site. The two guanosines form a Gsyn:Ganti pair solving the steric problem by flipping the 2-amino group of the guanosine adjacent to the editing site into the major groove. Also, duplexes with 2'-deoxyadenosine and 3-deaza-2'-deoxyadenosine displayed increased editing efficiency, suggesting the formation of a Gsyn:AH+anti pair. This was supported by X-ray crystallography of an ADAR complex with RNA bearing a G:3-deaza dA pair. This study shows how non-Watson-Crick pairing in duplex RNA can facilitate ADAR editing enabling the design of next generation guide strands for therapeutic RNA editing.

PubMed: 36243986
DOI: 10.1093/nar/gkac897

実験手法

X-RAY DIFFRACTION (2.8 Å)