9IX1

Crystal structure of the mouse RIP3 kinase domain in complexed with PP2

9IX1 の概要

• エントリーDOI: 10.2210/pdb9ix1/pdb
• 分子名称: Receptor-interacting serine/threonine-protein kinase 3, 1-TERT-BUTYL-3-(4-CHLORO-PHENYL)-1H-PYRAZOLO[3,4-D]PYRIMIDIN-4-YLAMINE (3 entities in total)
• 機能のキーワード: mouse rip3 kinase domain, inhibitor, complex, transferase
• 由来する生物種: Mus musculus (house mouse)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 73032.22

構造登録者

Xie, H.,Su, H.X.,Li, M.J.,Xu, Y.C. (登録日: 2024-07-26, 公開日: 2025-05-07, 最終更新日: 2025-05-21)

主引用文献

Su, H.,Chen, G.,Xie, H.,Li, W.,Xiong, M.,He, J.,Hu, H.,Zhao, W.,Shao, Q.,Li, M.,Zhao, Q.,Xu, Y.
Structure-based design of potent and selective inhibitors targeting RIPK3 for eliminating on-target toxicity in vitro.
Nat Commun, 16:4288-4288, 2025

PubMed Abstract: The essential role of RIPK3 in necroptosis makes its inhibition a promising therapeutic strategy. However, the development of RIPK3 inhibitors has been hampered by on-target apoptosis and limited kinase selectivity. Inspired by the R69H mutation, which prevents on-target apoptosis by disrupting RIPK3 dimerization, we design LK-series inhibitors that effectively inhibit RIPK3 in biochemical assays and block TNF-α-induced necroptosis in both mouse L929 and human HT29 cells without inducing apoptosis. The representative compound, LK01003, shows high selectivity across a panel of 379 kinases. Our structural studies reveal that LK compounds act as Type I inhibitors, engaging a unique hydrophobic site and stabilizing an inactive conformation of RIPK3. Moreover, several type II inhibitors are also revealed to maintain RIPK3 in the inactive conformation and do not induce on-target apoptosis. These findings suggest a promising strategy for rational design of safe and selective inhibitors by locking the inactive conformation of RIPK3.

PubMed: 40341069
DOI: 10.1038/s41467-025-59432-8

実験手法

X-RAY DIFFRACTION (2.31 Å)