5UZZ

Structure of wild type pre-miR21 apical loop

5UZZ の概要

• エントリーDOI: 10.2210/pdb5uzz/pdb
• 関連するPDBエントリー: 5UZT 5V29
• NMR情報: BMRB: 30258
• 分子名称: pre-miR21, 14-mer Peptide (2 entities in total)
• 機能のキーワード: microrna mir-21 oncomir pre-mirna, transport protein-rna complex, transport protein/rna
• 由来する生物種: Homo sapiens; 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 11725.12

構造登録者

Shortridge, M.D.,Varani, G. (登録日: 2017-02-27, 公開日: 2017-06-14, 最終更新日: 2024-11-06)

主引用文献

Shortridge, M.D.,Walker, M.J.,Pavelitz, T.,Chen, Y.,Yang, W.,Varani, G.
A Macrocyclic Peptide Ligand Binds the Oncogenic MicroRNA-21 Precursor and Suppresses Dicer Processing.
ACS Chem. Biol., 12:1611-1620, 2017

PubMed Abstract: MicroRNAs (miRNAs) help orchestrate cellular growth and survival through post-transcriptional mechanisms. The dysregulation of miRNA biogenesis can lead to cellular growth defects and chemotherapeutic resistance and plays a direct role in the development of many chronic diseases. Among these RNAs, miR-21 is consistently overexpressed in most human cancers, leading to the down-regulation of key tumor-suppressing and pro-apoptotic factors, suggesting that inhibition of miR-21 biogenesis could reverse these negative effects. However, targeted inhibition of miR-21 using small molecules has had limited success. To overcome difficulties in targeting RNA secondary structure with small molecules, we developed a class of cyclic β-hairpin peptidomimetics which bind to RNA stem-loop structures, such as miRNA precursors, with potent affinity and specificity. We screened an existing cyclic peptide library and discovered a lead structure which binds to pre-miR21 with K = 200 nM and prefers it over other pre-miRNAs. The NMR structure of the complex shows that the peptide recognizes the Dicer cleavage site and alters processing of the precursor to the mature miRNA in vitro and in cultured cells. The structure provides a rationale for the peptide binding activity and clear guidance for further improvements in affinity and targeting.

PubMed: 28437065
DOI: 10.1021/acschembio.7b00180

実験手法

SOLUTION NMR