8THQ

Nonamer RNA bound to hAgo2-PAZ

8THQ の概要

• エントリーDOI: 10.2210/pdb8thq/pdb
• 分子名称: Protein argonaute-2, RNA (5'-R(*CP*GP*UP*GP*AP*CP*UP*CP*U)-3') (3 entities in total)
• 機能のキーワード: h-ago2-paz, rna, loopmerna, paz domain, 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: 35151.62

構造登録者

Pallan, P.S.,Harp, J.M.,Egli, M. (登録日: 2023-07-17, 公開日: 2024-10-16)

主引用文献

Aluri, K.C.,Datta, D.,Waldron, S.,Taneja, N.,Qin, J.,Donnelly, D.P.,Theile, C.S.,Guenther, D.C.,Lei, L.,Harp, J.M.,Pallan, P.S.,Egli, M.,Zlatev, I.,Manoharan, M.
Single-Stranded Hairpin Loop RNAs (loopmeRNAs) Potently Induce Gene Silencing through the RNA Interference Pathway.
J.Am.Chem.Soc., 2024

PubMed Abstract: Synthetic small interfering RNAs conjugated to trivalent -acetylgalactosamine (GalNAc) are clinically validated drugs for treatment of liver diseases. Incorporation of phosphorothioate linkages and ribose modifications are necessary for stability, potency, and duration of pharmacology. Although multiple alternative siRNA designs such as Dicer-substrate RNA, shRNA, and circular RNA have been evaluated in vitro and in preclinical studies with some success, clinical applications of these designs are limited as it is difficult to incorporate chemical modifications in these designs. An alternative siRNA design that can incorporate chemical modifications through straightforward synthesis without compromising potency will significantly advance the field. Here, we report a facile synthesis of GalNAc ligand-containing single-stranded loop hairpin RNAs (loopmeRNAs) with clinically relevant chemical modifications. We evaluated the efficiency of novel loopmeRNA designs in vivo and correlated their structure-activity relationship with the support of in vitro metabolism data. Sequences and chemical modifications in the loop region of the loopmeRNA design were optimized for maximal potency. Our studies demonstrate that loopmeRNAs can efficiently silence expression of target genes with comparable efficacy to conventional double-stranded siRNAs but reduced environmental and regulatory burdens.

PubMed: 39373383
DOI: 10.1021/jacs.4c07902

実験手法

X-RAY DIFFRACTION (2.41 Å)