Crystal structure of catalytic domain of TACE with the first hydantoin inhibitor occupying the S1' pocket
[ADA17_HUMAN] Defects in ADAM17 are a cause of neonatal inflammatory skin and bowel disease (NISBD) [MIM:614328]. NISBD is a disorder characterized by inflammatory features with neonatal onset, involving the skin, hair, and gut. The skin lesions involve perioral and perianal erythema, psoriasiform erythroderma, with flares of erythema, scaling, and widespread pustules. Gastrointestinal symptoms include malabsorptive diarrhea that is exacerbated by intercurrent gastrointestinal infections. The hair is short or broken, and the eyelashes and eyebrows are wiry and disorganized.
[ADA17_HUMAN] Cleaves the membrane-bound precursor of TNF-alpha to its mature soluble form. Responsible for the proteolytical release of soluble JAM3 from endothelial cells surface. Responsible for the proteolytic release of several other cell-surface proteins, including p75 TNF-receptor, interleukin 1 receptor type II, p55 TNF-receptor, transforming growth factor-alpha, L-selectin, growth hormone receptor, MUC1 and the amyloid precursor protein. Also involved in the activation of Notch pathway (By similarity). 
Publication Abstract from PubMed
We disclose inhibitors of TNF-alpha converting enzyme (TACE) designed around a hydantoin zinc binding moiety. Crystal structures of inhibitors bound to TACE revealed monodentate coordination of the hydantoin to the zinc. SAR, X-ray, and modeling designs are described. To our knowledge, these are the first reported X-ray structures of TACE with a hydantoin zinc ligand.
Discovery and SAR of hydantoin TACE inhibitors.,Yu W, Guo Z, Orth P, Madison V, Chen L, Dai C, Feltz RJ, Girijavallabhan VM, Kim SH, Kozlowski JA, Lavey BJ, Li D, Lundell D, Niu X, Piwinski JJ, Popovici-Muller J, Rizvi R, Rosner KE, Shankar BB, Shih NY, Siddiqui MA, Sun J, Tong L, Umland S, Wong MK, Yang DY, Zhou G Bioorg Med Chem Lett. 2010 Mar 15;20(6):1877-80. Epub 2010 Feb 4. PMID:20172725
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