6HHO

Crystal structure of RIP1 kinase in complex with GSK547

Summary for 6HHO

• Entry DOI: 10.2210/pdb6hho/pdb
• Descriptor: 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)
• Functional Keywords: inhibitor, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 69990.60

Authors

Thorpe, J.H.,Harris, P.A. (deposition date: 2018-08-28, release date: 2018-12-12, Last modification date: 2024-01-17)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (3.49 Å)