5JPV

Efficient targeting of the asialoglycoprotein receptor by polyvalent display of a compact galactoseamine mimic

5JPV の概要

• エントリーDOI: 10.2210/pdb5jpv/pdb
• 関連するBIRD辞書のPRD_ID: PRD_900008
• 分子名称: Asialoglycoprotein receptor 1, beta-D-galactopyranose-(1-4)-alpha-D-glucopyranose, CALCIUM ION, ... (5 entities in total)
• 機能のキーワード: asialoglycoprotein receptor, carbohydrates, liver targeting, signaling protein
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Isoform H1a: Membrane; Single-pass type II membrane protein. Isoform H1b: Secreted : P07306
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 34983.65

構造登録者

Liu, S. (登録日: 2016-05-04, 公開日: 2017-06-14, 最終更新日: 2024-11-20)

主引用文献

Sanhueza, C.A.,Baksh, M.M.,Thuma, B.,Roy, M.D.,Dutta, S.,Preville, C.,Chrunyk, B.A.,Beaumont, K.,Dullea, R.,Ammirati, M.,Liu, S.,Gebhard, D.,Finley, J.E.,Salatto, C.T.,King-Ahmad, A.,Stock, I.,Atkinson, K.,Reidich, B.,Lin, W.,Kumar, R.,Tu, M.,Menhaji-Klotz, E.,Price, D.A.,Liras, S.,Finn, M.G.,Mascitti, V.
Efficient Liver Targeting by Polyvalent Display of a Compact Ligand for the Asialoglycoprotein Receptor.
J. Am. Chem. Soc., 139:3528-3536, 2017

PubMed Abstract: A compact and stable bicyclic bridged ketal was developed as a ligand for the asialoglycoprotein receptor (ASGPR). This compound showed excellent ligand efficiency, and the molecular details of binding were revealed by the first X-ray crystal structures of ligand-bound ASGPR. This analogue was used to make potent di- and trivalent binders of ASGPR. Extensive characterization of the function of these compounds showed rapid ASGPR-dependent cellular uptake in vitro and high levels of liver/plasma selectivity in vivo. Assessment of the biodistribution in rodents of a prototypical Alexa647-labeled trivalent conjugate showed selective hepatocyte targeting with no detectable distribution in nonparenchymal cells. This molecule also exhibited increased ASGPR-directed hepatocellular uptake and prolonged retention compared to a similar GalNAc derived trimer conjugate. Selective release in the liver of a passively permeable small-molecule cargo was achieved by retro-Diels-Alder cleavage of an oxanorbornadiene linkage, presumably upon encountering intracellular thiol. Therefore, the multicomponent construct described here represents a highly efficient delivery vehicle to hepatocytes.

PubMed: 28230359
DOI: 10.1021/jacs.6b12964

実験手法

X-RAY DIFFRACTION (1.9 Å)