| Structural highlights
Disease
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.[1]
Function
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).[2] [3]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
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[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Blaydon DC, Biancheri P, Di WL, Plagnol V, Cabral RM, Brooke MA, van Heel DA, Ruschendorf F, Toynbee M, Walne A, O'Toole EA, Martin JE, Lindley K, Vulliamy T, Abrams DJ, MacDonald TT, Harper JI, Kelsell DP. Inflammatory skin and bowel disease linked to ADAM17 deletion. N Engl J Med. 2011 Oct 20;365(16):1502-8. doi: 10.1056/NEJMoa1100721. PMID:22010916 doi:10.1056/NEJMoa1100721
- ↑ Thathiah A, Blobel CP, Carson DD. Tumor necrosis factor-alpha converting enzyme/ADAM 17 mediates MUC1 shedding. J Biol Chem. 2003 Jan 31;278(5):3386-94. Epub 2002 Nov 18. PMID:12441351 doi:10.1074/jbc.M208326200
- ↑ Rabquer BJ, Amin MA, Teegala N, Shaheen MK, Tsou PS, Ruth JH, Lesch CA, Imhof BA, Koch AE. Junctional adhesion molecule-C is a soluble mediator of angiogenesis. J Immunol. 2010 Aug 1;185(3):1777-85. doi: 10.4049/jimmunol.1000556. Epub 2010, Jun 30. PMID:20592283 doi:10.4049/jimmunol.1000556
- ↑ 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. Discovery and SAR of hydantoin TACE inhibitors. Bioorg Med Chem Lett. 2010 Mar 15;20(6):1877-80. Epub 2010 Feb 4. PMID:20172725 doi:10.1016/j.bmcl.2010.01.148
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