7C6B

Crystal structure of Ago2 MID domain in complex with 6-(3-(2-carboxyethyl)phenyl)purine riboside monophosphate

7C6B の概要

• エントリーDOI: 10.2210/pdb7c6b/pdb
• 関連するPDBエントリー: 6L45
• 分子名称: Protein argonaute-2, 3-[3-[9-[(2R,3R,4S,5R)-3,4-bis(oxidanyl)-5-(phosphonooxymethyl)oxolan-2-yl]purin-6-yl]phenyl]propanoic acid, PHOSPHATE ION, ... (4 entities in total)
• 機能のキーワード: argonaute, mid domain, ribonucleoprotein, rna-binding, rna-mediated gene silencing, translation regulation, rna binding protein
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 48026.62

構造登録者

Suzuki, M.,Takahashi, Y.,Saito, J.,Miyagi, H.,Shinohara, F. (登録日: 2020-05-21, 公開日: 2020-11-25, 最終更新日: 2023-11-29)

主引用文献

Shinohara, F.,Oashi, T.,Harumoto, T.,Nishikawa, T.,Takayama, Y.,Miyagi, H.,Takahashi, Y.,Nakajima, T.,Sawada, T.,Koda, Y.,Makino, A.,Sato, A.,Hamaguchi, K.,Suzuki, M.,Yamamoto, J.,Tomari, Y.,Saito, J.I.
siRNA potency enhancement via chemical modifications of nucleotide bases at the 5'-end of the siRNA guide strand.
Rna, 27:163-173, 2021

PubMed Abstract: Small interfering RNAs (siRNAs) can be utilized not only as functional biological research tools but also as therapeutic agents. For the clinical use of siRNA as drugs, various chemical modifications have been used to improve the activity of siRNA drugs, and further chemical modifications are expected to improve the utility of siRNA therapeutics. As the 5' nucleobase of the guide strand affects the interaction between an siRNA and AGO2 and target cleavage activity, structural optimization of this specific position may be a useful strategy for improving siRNA activity. Here, using the in silico model of the complex between human AGO2 MID domain and nucleoside monophosphates, we screened and synthesized an original adenine-derived analog, 6-(3-(2-carboxyethyl)phenyl)purine (6-mCEPh-purine), that fits better than the natural nucleotide bases into the MID domain of AGO2. Introduction of the 6-mCEPh-purine analog at the 5'-end of the siRNA guide strand significantly enhanced target knockdown activity in both cultured cell lines and in vivo animal models. Our findings can help expand strategies for rationally optimizing siRNA activity via chemical modifications of nucleotide bases.

PubMed: 33177188
DOI: 10.1261/rna.073783.119

実験手法

X-RAY DIFFRACTION (1.7 Å)