8URF

Crystal Structure of human ASGR2 CRD (Carbohydrate Recognition Domain) bound to 8G8 Fab

Summary for 8URF

• Entry DOI: 10.2210/pdb8urf/pdb
• Descriptor: 8G8 Fab Light Chain, 8G8 Fab Heavy Chain, Asialoglycoprotein receptor 2, ... (7 entities in total)
• Functional Keywords: asgr, asgpr, asgr2, asgr1, fab, 8g8, abtac, lytac, antibody, sugar binding protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 3
• Total formula weight: 67940.49

Authors

Sampathumar, P.,Li, Y. (deposition date: 2023-10-25, release date: 2024-06-19, Last modification date: 2024-10-30)

Primary citation

Sampathkumar, P.,Jung, H.,Chen, H.,Zhang, Z.,Suen, N.,Yang, Y.,Huang, Z.,Lopez, T.,Benisch, R.,Lee, S.J.,Ye, J.,Yeh, W.C.,Li, Y.
Targeted protein degradation systems to enhance Wnt signaling.
Elife, 13:-, 2024

PubMed Abstract: Molecules that facilitate targeted protein degradation (TPD) offer great promise as novel therapeutics. The human hepatic lectin asialoglycoprotein receptor (ASGR) is selectively expressed on hepatocytes. We have previously engineered an anti-ASGR1 antibody-mutant RSPO2 (RSPO2RA) fusion protein (called SWEETS) to drive tissue-specific degradation of ZNRF3/RNF43 E3 ubiquitin ligases, which achieved hepatocyte-specific enhanced Wnt signaling, proliferation, and restored liver function in mouse models, and an antibody-RSPO2RA fusion molecule is currently in human clinical trials. In the current study, we identified two new ASGR1- and ASGR1/2-specific antibodies, 8M24 and 8G8. High-resolution crystal structures of ASGR1:8M24 and ASGR2:8G8 complexes revealed that these antibodies bind to distinct epitopes on opposing sides of ASGR, away from the substrate-binding site. Both antibodies enhanced Wnt activity when assembled as SWEETS molecules with RSPO2RA through specific effects sequestering E3 ligases. In addition, 8M24-RSPO2RA and 8G8-RSPO2RA efficiently downregulate ASGR1 through TPD mechanisms. These results demonstrate the possibility of combining different therapeutic effects and degradation mechanisms in a single molecule.

PubMed: 38847394
DOI: 10.7554/eLife.93908

Experimental method

X-RAY DIFFRACTION (1.9 Å)