9IWY

Crystal structure of the mouse RIP3 kinase domain in complexed with LK01003

This is a non-PDB format compatible entry.

Summary for 9IWY

• Entry DOI: 10.2210/pdb9iwy/pdb
• Descriptor: Receptor-interacting serine/threonine-protein kinase 3, 2-cyclopentyl-~{N}-(6-propan-2-ylsulfonylquinolin-4-yl)-1,3-benzothiazol-5-amine (3 entities in total)
• Functional Keywords: mouse rip3 kinase domain, inhibitor, complex, transferase
• Biological source: Mus musculus (house mouse)
• Total number of polymer chains: 2
• Total formula weight: 73329.86

Authors

Xie, H.,Su, H.X.,Li, M.J.,Xu, Y.C. (deposition date: 2024-07-26, release date: 2025-05-07, Last modification date: 2025-05-21)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.52 Å)