9IVU

Crystal structure of Ang1-A451D receptor binding domain

9IVU の概要

• エントリーDOI: 10.2210/pdb9ivu/pdb
• 分子名称: Angiopoietin-1 (2 entities in total)
• 機能のキーワード: angiopoietin 1, cell adhesion
• 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: 26232.32

構造登録者

Wang, R.,Huang, M.D.,Jiang, L.G. (登録日: 2024-07-24, 公開日: 2025-07-02)

主引用文献

Wang, R.,Li, H.,Xie, Z.,Huang, M.,Xu, P.,Yuan, C.,Li, J.,Flaumenhaft, R.,Huang, M.,Jiang, L.
Development of a recombinant Ang1 variant with enhanced Tie2 binding and its application to attenuate sepsis in mice.
Sci Adv, 11:eads1796-eads1796, 2025

PubMed Abstract: The angiopoietin (Ang)-Tie axis, critical for endothelial cell function and vascular development, is a promising therapeutic target for treating vascular disorders and inflammatory conditions like sepsis. This study aimed to enhance the binding affinity of recombinant Ang1 variants to the Tie2 and explore their therapeutic potential. Structural insights from the Ang1-Tie2 complex enabled the identification of key residues within the Ang1 receptor binding domain (RBD) critical for Tie2 interaction. Molecular dynamics simulations revealed that MetArg (M436R) and AlaAsp (A451D) could improve Ang1's Tie2 binding affinity. One variant, Ang1-RBD, demonstrated a 100-fold increase compared to the wild type. Cellular assays revealed that Ang1 enhanced Tie2 phosphorylation, promoting endothelial cell migration and tube formation. In vivo, this variant effectively reduced inflammatory cytokines and attenuated organ damage in septic mice. These findings highlight Ang1 as a promising therapeutic candidate for vascular diseases, offering notable clinical potential for mitigating sepsis-related vascular dysfunction.

PubMed: 39813336
DOI: 10.1126/sciadv.ads1796

実験手法

X-RAY DIFFRACTION (2.28 Å)