8TS0

Crystal Structure of human ASGR1 CRD (Carbohydrate Recognition Domain) bound to 8M24 Fab

8TS0 の概要

• エントリーDOI: 10.2210/pdb8ts0/pdb
• 分子名称: 8M24 Fab Heavy chain, 8M24 Fab Light chain, Asialoglycoprotein receptor 1, ... (6 entities in total)
• 機能のキーワード: asgr, asgpr, 8m24, endocytosis, sugar binding protein, sugar binding protein-immune system complex, sugar binding protein/immune system
• 由来する生物種: Homo sapiens; 詳細
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 69229.42

構造登録者

Sampathkumar, P.,Li, Y. (登録日: 2023-08-10, 公開日: 2024-06-19, 最終更新日: 2024-11-13)

主引用文献

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

実験手法

X-RAY DIFFRACTION (1.7 Å)