3lea

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{{STRUCTURE_3lea| PDB=3lea | SCENE= }}
 
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===Crystal structure of the catalytic domain of TACE with Isoindolinone-biphenyl-hydantoin inhibitor===
 
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{{ABSTRACT_PUBMED_20663669}}
 
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==Disease==
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==Crystal structure of the catalytic domain of TACE with Isoindolinone-biphenyl-hydantoin inhibitor==
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[[http://www.uniprot.org/uniprot/ADA17_HUMAN ADA17_HUMAN]] Defects in ADAM17 are a cause of neonatal inflammatory skin and bowel disease (NISBD) [MIM:[http://omim.org/entry/614328 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.<ref>PMID:22010916</ref>
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<StructureSection load='3lea' size='340' side='right'caption='[[3lea]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[3lea]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3LEA OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3LEA FirstGlance]. <br>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=IPA:ISOPROPYL+ALCOHOL'>IPA</scene>, <scene name='pdbligand=Z93:2-{[(4R)-2,5-DIOXO-4-(4-PYRIDIN-3-YLPHENYL)IMIDAZOLIDIN-4-YL]METHYL}-6-METHOXY-1-OXO-1H-ISOINDOLIUM'>Z93</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3lea FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3lea OCA], [https://pdbe.org/3lea PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3lea RCSB], [https://www.ebi.ac.uk/pdbsum/3lea PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3lea ProSAT]</span></td></tr>
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</table>
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== Disease ==
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[https://www.uniprot.org/uniprot/ADA17_HUMAN ADA17_HUMAN] Defects in ADAM17 are a cause of neonatal inflammatory skin and bowel disease (NISBD) [MIM:[https://omim.org/entry/614328 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.<ref>PMID:22010916</ref>
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== Function ==
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[https://www.uniprot.org/uniprot/ADA17_HUMAN 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).<ref>PMID:12441351</ref> <ref>PMID:20592283</ref>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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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.
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==Function==
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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<ref>PMID:20663669</ref>
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[[http://www.uniprot.org/uniprot/ADA17_HUMAN 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).<ref>PMID:12441351</ref><ref>PMID:20592283</ref>
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==About this Structure==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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[[3lea]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3LEA OCA].
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</div>
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<div class="pdbe-citations 3lea" style="background-color:#fffaf0;"></div>
==See Also==
==See Also==
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*[[A Disintegrin And Metalloproteinase|A Disintegrin And Metalloproteinase]]
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*[[A Disintegrin And Metalloproteinase 3D structures|A Disintegrin And Metalloproteinase 3D structures]]
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== References ==
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==Reference==
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<references/>
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<ref group="xtra">PMID:020663669</ref><references group="xtra"/><references/>
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__TOC__
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[[Category: ADAM 17 endopeptidase]]
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: Orth, P.]]
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[[Category: Large Structures]]
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[[Category: Glycoprotein]]
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[[Category: Orth P]]
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[[Category: Hydrolase]]
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[[Category: Membrane]]
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[[Category: Metal-binding]]
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[[Category: Metalloprotease]]
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[[Category: Notch signaling pathway]]
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[[Category: Phosphoprotein]]
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[[Category: Protease]]
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[[Category: Transmembrane]]
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[[Category: Zymogen]]
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Current revision

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

PDB ID 3lea

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