5t8o | pdb_00005t8o

Crystal structure of murine NF-kappaB inducing kinase (NIK) bound to Imidazobenzoxepin Compound 3

spinqualitylabelsall models 5t8o, resolution 2.41Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5t8o is a 2 chain structure with sequence from Lk3 transgenic mice. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: 76Z, SO4 Gene: Map3k14, Nik (LK3 transgenic mice) Activity: Mitogen-activated protein kinase kinase kinase, with EC number 2.7.11.25 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [M3K14_MOUSE] Lymphotoxin beta-activated kinase which seems to be exclusively involved in the activation of NF-kappa-B and its transcriptional activity. Promotes proteolytic processing of NFKB2/P100, which leads to activation of NF-kappa-B via the non-canonical pathway. Could act in a receptor-selective manner. Publication Abstract from PubMed We report here structure-guided optimization of a novel series of NF-kappaB inducing kinase (NIK) inhibitors. Starting from a modestly potent, low molecular weight lead, activity was improved by designing a type 11/2 binding mode that accessed a back pocket past the methionine-471 gatekeeper. Divergent binding modes in NIK and PI3K were exploited to dampen PI3K inhibition while maintaining NIK inhibition within these series. Potent compounds were discovered that selectively inhibit the nuclear translocation of NF-kappaB2 (p52/REL-B) but not canonical NF-kappaB1 (REL-A/p50). Structure-Based Design of Tricyclic NF-kappaB Inducing Kinase (NIK) Inhibitors That Have High Selectivity over Phosphoinositide-3-kinase (PI3K).,Castanedo GM, Blaquiere N, Beresini M, Bravo B, Brightbill H, Chen J, Cui HF, Eigenbrot C, Everett C, Feng J, Godemann R, Gogol E, Hymowitz S, Johnson A, Kayagaki N, Kohli PB, Knuppel K, Kraemer J, Kruger S, Loke P, McEwan P, Montalbetti C, Roberts DA, Smith M, Steinbacher S, Sujatha-Bhaskar S, Takahashi R, Wang X, Wu LC, Zhang Y, Staben ST J Med Chem. 2017 Jan 12. doi: 10.1021/acs.jmedchem.6b01363. PMID:28005357 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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