3l0v

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{{STRUCTURE_3l0v| PDB=3l0v | SCENE= }}
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==Crystal structure of catalytic domain of TACE with the first hydantoin inhibitor occupying the S1' pocket==
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===Crystal structure of catalytic domain of TACE with the first hydantoin inhibitor occupying the S1' pocket===
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<StructureSection load='3l0v' size='340' side='right' caption='[[3l0v]], [[Resolution|resolution]] 1.75&Aring;' scene=''>
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{{ABSTRACT_PUBMED_20172725}}
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== Structural highlights ==
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<table><tr><td colspan='2'>[[3l0v]] 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=3L0V OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3L0V FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=724:(5R)-5-[(5-METHOXY-3-OXO-1,3-DIHYDRO-2H-INDAZOL-2-YL)METHYL]-5-METHYLIMIDAZOLIDINE-2,4-DIONE'>724</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1bkc|1bkc]], [[3kmc|3kmc]], [[3l0t|3l0t]], [[3le9|3le9]], [[3lea|3lea]]</td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ADAM17, CSVP, TACE ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</td></tr>
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<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/ADAM_17_endopeptidase ADAM 17 endopeptidase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.24.86 3.4.24.86] </span></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3l0v FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3l0v OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3l0v RCSB], [http://www.ebi.ac.uk/pdbsum/3l0v PDBsum]</span></td></tr>
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</table>
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== Disease ==
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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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== Function ==
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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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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/l0/3l0v_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/chain_selection.php?pdb_ID=2ata ConSurf].
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<div style="clear:both"></div>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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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.
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==Disease==
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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<ref>PMID:20172725</ref>
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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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==Function==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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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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</div>
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==About this Structure==
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[[3l0v]] 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=3L0V OCA].
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==See Also==
==See Also==
*[[A Disintegrin And Metalloproteinase|A Disintegrin And Metalloproteinase]]
*[[A Disintegrin And Metalloproteinase|A Disintegrin And Metalloproteinase]]
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== References ==
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==Reference==
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<references/>
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<ref group="xtra">PMID:020172725</ref><references group="xtra"/><references/>
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__TOC__
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</StructureSection>
[[Category: ADAM 17 endopeptidase]]
[[Category: ADAM 17 endopeptidase]]
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: Orth, P.]]
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[[Category: Orth, P]]
[[Category: Hydrolase-hydrolase inhibitor complex]]
[[Category: Hydrolase-hydrolase inhibitor complex]]
[[Category: Metal-binding]]
[[Category: Metal-binding]]

Revision as of 17:43, 18 December 2014

Crystal structure of catalytic domain of TACE with the first hydantoin inhibitor occupying the S1' pocket

3l0v, resolution 1.75Å

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