4l52
From Proteopedia
Crystal Structure of 1-(4-{4-[7-amino-2-(1,2,3-benzothiadiazol-7-yl)furo[2,3-c]pyridin-4-yl]-1H-pyrazol-1-yl}piperidin-1-yl)ethan-1-one bound to TAK1-TAB1
Structural highlights
FunctionTAB1_HUMAN May be an important signaling intermediate between TGFB receptors and MAP3K7/TAK1. May play an important role in mammalian embryogenesis.[1] M3K7_HUMAN Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. Plays an important role in the cascades of cellular responses evoked by changes in the environment. Mediates signal transduction of TRAF6, various cytokines including interleukin-1 (IL-1), transforming growth factor-beta (TGFB), TGFB-related factors like BMP2 and BMP4, toll-like receptors (TLR), tumor necrosis factor receptor CD40 and B-cell receptor (BCR). Ceramides are also able to activate MAP3K7/TAK1. Once activated, acts as an upstream activator of the MKK/JNK signal transduction cascade and the p38 MAPK signal transduction cascade through the phosphorylation and activation of several MAP kinase kinases like MAP2K1/MEK1, MAP2K3/MKK3, MAP2K6/MKK6 and MAP2K7/MKK7. These MAP2Ks in turn activate p38 MAPKs, c-jun N-terminal kinases (JNKs) and I-kappa-B kinase complex (IKK). Both p38 MAPK and JNK pathways control the transcription factors activator protein-1 (AP-1), while nuclear factor-kappa B is activated by IKK. MAP3K7 activates also IKBKB and MAPK8/JNK1 in response to TRAF6 signaling and mediates BMP2-induced apoptosis. In osmotic stress signaling, plays a major role in the activation of MAPK8/JNK1, but not that of NF-kappa-B. Promotes TRIM5 capsid-specific restriction activity.[2] [3] [4] [5] [6] [7] [8] [9] Publication Abstract from PubMedThe discovery and potency optimization of a series of 7-aminofuro[2,3-c]pyridine inhibitors of TAK1 is described. Micromolar hits taken from high-throughput screening were optimized for biochemical and cellular mechanistic potency to approximately 10nM, as exemplified by compound 12az. Application of structure-based drug design aided by co-crystal structures of TAK1 with inhibitors significantly shortened the number of iterations required for the optimization. Discovery and optimization of 7-aminofuro[2,3-c]pyridine inhibitors of TAK1.,Hornberger KR, Berger DM, Crew AP, Dong H, Kleinberg A, Li AH, Medeiros MR, Mulvihill MJ, Siu K, Tarrant J, Wang J, Weng F, Wilde VL, Albertella M, Bittner M, Cooke A, Gray MJ, Maresca P, May E, Meyn P, Peick W Jr, Romashko D, Tanowitz M, Tokar B Bioorg Med Chem Lett. 2013 Aug 15;23(16):4517-22. doi:, 10.1016/j.bmcl.2013.06.053. Epub 2013 Jun 25. PMID:23850198[10] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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Categories: Homo sapiens | Large Structures | Crew AP | Hornberger KR | Jestel A | Maskos K | Moertl M | Wang J
