5JQ1
Efficient targeting of the asialoglycoprotein receptor by polyvalent display of a compact galactosamine mimic
Summary for 5JQ1
| Entry DOI | 10.2210/pdb5jq1/pdb |
| Related | 5JPV |
| Descriptor | Asialoglycoprotein receptor 1, CALCIUM ION, N-[(1S,2R,3R,4R,5S)-2,3-dihydroxy-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]octan-4-yl]acetamide, ... (5 entities in total) |
| Functional Keywords | asialoglycoprotein receptor, carbohydrates, liver targeting, sugar binding protein |
| Biological source | Homo sapiens (Human) |
| Cellular location | Isoform H1a: Membrane; Single-pass type II membrane protein. Isoform H1b: Secreted : P07306 |
| Total number of polymer chains | 2 |
| Total formula weight | 34765.50 |
| Authors | |
| Primary citation | 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 Cited by 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: 28230359DOI: 10.1021/jacs.6b12964 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.83 Å) |
Structure validation
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