6HHO

Crystal structure of RIP1 kinase in complex with GSK547

6HHO の概要

• エントリーDOI: 10.2210/pdb6hho/pdb
• 分子名称: Receptor-interacting serine/threonine-protein kinase 1, 6-[4-[(5~{S})-5-[3,5-bis(fluoranyl)phenyl]pyrazolidin-1-yl]carbonylpiperidin-1-yl]pyrimidine-4-carbonitrile (2 entities in total)
• 機能のキーワード: inhibitor, transferase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 69990.60

構造登録者

Thorpe, J.H.,Harris, P.A. (登録日: 2018-08-28, 公開日: 2018-12-12, 最終更新日: 2024-01-17)

主引用文献

Wang, W.,Marinis, J.M.,Beal, A.M.,Savadkar, S.,Wu, Y.,Khan, M.,Taunk, P.S.,Wu, N.,Su, W.,Wu, J.,Ahsan, A.,Kurz, E.,Chen, T.,Yaboh, I.,Li, F.,Gutierrez, J.,Diskin, B.,Hundeyin, M.,Reilly, M.,Lich, J.D.,Harris, P.A.,Mahajan, M.K.,Thorpe, J.H.,Nassau, P.,Mosley, J.E.,Leinwand, J.,Kochen Rossi, J.A.,Mishra, A.,Aykut, B.,Glacken, M.,Ochi, A.,Verma, N.,Kim, J.I.,Vasudevaraja, V.,Adeegbe, D.,Almonte, C.,Bagdatlioglu, E.,Cohen, D.J.,Wong, K.K.,Bertin, J.,Miller, G.
RIP1 Kinase Drives Macrophage-Mediated Adaptive Immune Tolerance in Pancreatic Cancer.
Cancer Cell, 34:757-774.e7, 2018

PubMed Abstract: Pancreatic ductal adenocarcinoma (PDA) is characterized by immune tolerance and immunotherapeutic resistance. We discovered upregulation of receptor-interacting serine/threonine protein kinase 1 (RIP1) in tumor-associated macrophages (TAMs) in PDA. To study its role in oncogenic progression, we developed a selective small-molecule RIP1 inhibitor with high in vivo exposure. Targeting RIP1 reprogrammed TAMs toward an MHCIITNFαIFNγ immunogenic phenotype in a STAT1-dependent manner. RIP1 inhibition in TAMs resulted in cytotoxic T cell activation and T helper cell differentiation toward a mixed Th1/Th17 phenotype, leading to tumor immunity in mice and in organotypic models of human PDA. Targeting RIP1 synergized with PD1-and inducible co-stimulator-based immunotherapies. Tumor-promoting effects of RIP1 were independent of its co-association with RIP3. Collectively, our work describes RIP1 as a checkpoint kinase governing tumor immunity.

PubMed: 30423296
DOI: 10.1016/j.ccell.2018.10.006

実験手法

X-RAY DIFFRACTION (3.49 Å)