9G7D

Crystal structure of ASGPR with bound IMP

9G7D の概要

• エントリーDOI: 10.2210/pdb9g7d/pdb
• 分子名称: Asialoglycoprotein receptor 1, CALCIUM ION, INOSINIC ACID, ... (4 entities in total)
• 機能のキーワード: asialo glycoprotein receptor, sugar binding, natural ligand complex, sirna targeting, sugar binding protein
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 18453.02

構造登録者

Schreuder, H.A.,Hofmeister, A. (登録日: 2024-07-20, 公開日: 2025-03-19, 最終更新日: 2025-04-09)

主引用文献

Hofmeister, A.,Jahn-Hofmann, K.,Brunner, B.,Helms, M.,Metz-Weidmann, C.,Poeverlein, C.,Zech, G.,Li, Z.,Hessler, G.,Schreuder, H.,Elshorst, B.,Krack, A.,Kurz, M.,Heubel, C.,Scheidler, S.
Trivalent siRNA-Conjugates with Guanosine as ASGPR-Binder Show Potent Knock-Down In Vivo.
J.Med.Chem., 68:6193-6209, 2025

PubMed Abstract: To increase the chemical space around the well-known GalNAc-ligand as ASGPR-binder, a high-throughput screening campaign was performed, testing approximately 550,000 compounds. After evaluation of the potential screening hits, only one compound, which showed high similarity with guanosine nucleosides, was chosen for further profiling. Crystal structure analysis revealed the coordination of the Ca-ion within the ASGPR-binding site by the -diol motif of the ribose unit as well as an additional π-π-interaction of the purine heterocycle to tryptophan-243. Based on these findings, guanosine was attached via the 5'-OH group to a recently described morpholino-based nucleotide using two different linker units. The resulting morpholino-guanosine building blocks were conjugated to the 5'-end of a literature-known transthyretin targeting small interfering RNA (siRNA), leading to trivalent siRNA-guanosine conjugates, which were tested for their TTR knockdown and exhibited similar potencies as the analogous GalNAc-conjugates in vitro and in vivo.

PubMed: 40052708
DOI: 10.1021/acs.jmedchem.4c02275

実験手法

X-RAY DIFFRACTION (1.588 Å)