Summary for 9GTG
| Entry DOI | 10.2210/pdb9gtg/pdb |
| Descriptor | Receptor-interacting serine/threonine-protein kinase 1, (5R)-5-[(7-chloro-1H-indol-3-yl)methyl]-3-methylimidazolidine-2,4-dione, ~{N}-[[(3~{S})-1-ethanoylpyrrolidin-3-yl]methyl]-~{N}-methyl-4-quinolin-7-yl-benzenesulfonamide, ... (4 entities in total) |
| Functional Keywords | ripk1, kinase, inhibitor, transferase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 2 |
| Total formula weight | 72594.44 |
| Authors | Petersen, J. (deposition date: 2024-09-17, release date: 2025-07-02, Last modification date: 2025-07-30) |
| Primary citation | Soday, L.,Seripracharat, C.,Gray, J.L.,Luz, A.F.S.,Howard, R.T.,Singh, R.,Burden, T.J.,Bernardini, E.,Mateus-Pinheiro, M.,Petersen, J.,Gunnarsson, A.,Gunnarsson, J.,Aagaard, A.,Sjogren, T.,Maslen, S.,Bartlett, E.J.,Iles, A.F.,Smith, D.M.,Scott, J.S.,Skehel, M.,Davis, A.M.,Ressurreicao, A.S.,Moreira, R.,Rodrigues, C.M.P.,Shenoy, A.R.,Tate, E.W. Discovery and Validation of a Novel Class of Necroptosis Inhibitors Targeting RIPK1. Acs Chem.Biol., 20:1527-1543, 2025 Cited by PubMed Abstract: Necroptosis is a form of programmed cell death that, when dysregulated, is associated with cancer and inflammatory and neurodegenerative diseases. Here, starting from hits identified from a phenotypic high-throughput screen for inhibitors of necroptosis, we synthesized a library of compounds containing a 7-phenylquinoline motif and validated their anti-necroptotic activity in a novel live-cell assay. Based on these data, we designed an optimized photoaffinity probe for target engagement studies and through biochemical and cell-based assays established receptor-interacting kinase 1 (RIPK1) as the cellular target, with inhibition of necroptosis arising from the prevention of RIPK1 autophosphorylation and activation. X-ray crystallography and mass spectrometry revealed that these compounds bind at the hinge region of the active conformation of RIPK1, establishing them as type I kinase inhibitors. In addition, we demonstrated synergy with type III kinase inhibitors, such as necrostatin-1 and found that lead compounds protected mice against acute inflammation in necroptosis models . Overall, we present a novel pharmacophore for inhibition of human RIPK1, a key protein involved in necroptosis, and provide a photoaffinity probe to explore RIPK1 target engagement in cells. PubMed: 40539767DOI: 10.1021/acschembio.5c00112 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.25 Å) |
Structure validation
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