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3lea

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3lea, resolution 2.00Å ()
Ligands: , ,
Gene: ADAM17, CSVP, TACE (Homo sapiens)
Activity: ADAM 17 endopeptidase, with EC number 3.4.24.86
Related: 1bkc, 3l0t, 3l0v, 3le9


Resources: FirstGlance, OCA, RCSB, PDBsum
Coordinates: save as pdb, mmCIF, xml


Contents

Crystal structure of the catalytic domain of TACE with Isoindolinone-biphenyl-hydantoin inhibitor

Publication Abstract from PubMed

We disclose further optimization of hydantoin TNF-alpha convertase enzyme (TACE) inhibitors. SAR with respect to the non-prime region of TACE active site was explored. A series of biaryl substituted hydantoin compounds was shown to have sub-nanomolar K(i), good rat PK, and good selectivity versus MMP-1, -2, -3, -7, -9, and -13.

Biaryl substituted hydantoin compounds as TACE inhibitors., Yu W, Tong L, Kim SH, Wong MK, Chen L, Yang DY, Shankar BB, Lavey BJ, Zhou G, Kosinski A, Rizvi R, Li D, Feltz RJ, Piwinski JJ, Rosner KE, Shih NY, Siddiqui MA, Guo Z, Orth P, Shah H, Sun J, Umland S, Lundell DJ, Niu X, Kozlowski JA, Bioorg Med Chem Lett. 2010 Sep 1;20(17):5286-9. Epub 2010 Jul 1. PMID:20663669

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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]

About this Structure

3lea is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA.

See Also

Reference

  • Yu W, Tong L, Kim SH, Wong MK, Chen L, Yang DY, Shankar BB, Lavey BJ, Zhou G, Kosinski A, Rizvi R, Li D, Feltz RJ, Piwinski JJ, Rosner KE, Shih NY, Siddiqui MA, Guo Z, Orth P, Shah H, Sun J, Umland S, Lundell DJ, Niu X, Kozlowski JA. Biaryl substituted hydantoin compounds as TACE inhibitors. Bioorg Med Chem Lett. 2010 Sep 1;20(17):5286-9. Epub 2010 Jul 1. PMID:20663669 doi:10.1016/j.bmcl.2010.06.134
  1. 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
  2. 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
  3. 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

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