3LHJ
Crystal Structure of p38a Mitogen-Activated Protein Kinase in Complex with a Pyrazolopyridinone Inhibitor.
Summary for 3LHJ
| Entry DOI | 10.2210/pdb3lhj/pdb |
| Related | 1YQJ 3DS6 3DT1 3GFE 3ITZ |
| Descriptor | Mitogen-activated protein kinase 14, N-cyclopropyl-3-[1-(2,4-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl]-4-methylbenzamide (3 entities in total) |
| Functional Keywords | serine/threonine-protein kinase, transferase, alternative splicing, atp-binding, cytoplasm, kinase, nucleotide-binding, nucleus, phosphoprotein, polymorphism |
| Biological source | Homo sapiens (human) |
| Cellular location | Cytoplasm (By similarity): Q16539 |
| Total number of polymer chains | 1 |
| Total formula weight | 42433.38 |
| Authors | Mohr, C.,Jordan, S. (deposition date: 2010-01-22, release date: 2010-04-14, Last modification date: 2024-02-21) |
| Primary citation | Pettus, L.H.,Wurz, R.P.,Xu, S.,Herberich, B.,Henkle, B.,Liu, Q.,McBride, H.J.,Mu, S.,Plant, M.H.,Saris, C.J.,Sherman, L.,Wong, L.M.,Chmait, S.,Lee, M.R.,Mohr, C.,Hsieh, F.,Tasker, A.S. Discovery and evaluation of 7-alkyl-1,5-bis-aryl-pyrazolopyridinones as highly potent, selective, and orally efficacious inhibitors of p38alpha mitogen-activated protein kinase. J.Med.Chem., 53:2973-2985, 2010 Cited by PubMed Abstract: The p38alpha mitogen-activated protein (MAP) kinase is a central signaling molecule in many proinflammatory pathways, regulating the cellular response to a multitude of external stimuli including heat, ultraviolet radiation, osmotic shock, and a variety of cytokines especially interleukin-1beta and tumor necrosis factor alpha. Thus, inhibitors of this enzyme are postulated to have significant therapeutic potential for the treatment of rheumatoid arthritis, inflammatory bowel disease, and Crohn's disease, as well as other diseases where aberrant cytokine signaling is the driver of disease. In this communication, we describe a novel class of 7-alkyl-1,5-bis-aryl-pyrazolopyridinone-based p38alpha inhibitors. In particular, compound 3f is highly potent in the enzyme and cell-based assays, selective in an Ambit kinase screen, and efficacious (ED(50) < or = 0.01 mg/kg) in the rat collagen induced arthritis (CIA) model. PubMed: 20218619DOI: 10.1021/jm100095x PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (3.31 Å) |
Structure validation
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