3g42

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{{STRUCTURE_3g42| PDB=3g42 | SCENE= }}
 
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===Crystal Structure of TACE with Tryptophan Sulfonamide Derivative Inhibitor===
 
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{{ABSTRACT_PUBMED_19410464}}
 
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==Disease==
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==Crystal Structure of TACE with Tryptophan Sulfonamide Derivative 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='3g42' size='340' side='right'caption='[[3g42]], [[Resolution|resolution]] 2.10&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[3g42]] is a 4 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=3G42 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3G42 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]] 2.1&#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=792:N-{[4-(BUT-2-YN-1-YLOXY)PHENYL]SULFONYL}-5-METHYL-D-TRYPTOPHAN'>792</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=3g42 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3g42 OCA], [https://pdbe.org/3g42 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3g42 RCSB], [https://www.ebi.ac.uk/pdbsum/3g42 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3g42 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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== 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/g4/3g42_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.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/main_output.php?pdb_ID=3g42 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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A novel series of non-hydroxamate tryptophan sulfonamide derivatives containing a butynyloxy P1' moiety was identified as inhibitors of TNF-alpha converting enzyme (TACE). The structure-activity relationship of the series was examined via substitution on the tryptophan indole ring. Of the compounds investigated, 2-(4-(but-2-ynyloxy)phenylsulfonamido)-3-(1-(4-methoxybenzyl)-1H-indol-3-y l)propanoic acid (12p) has the best in vitro potency against isolated TACE enzyme with an IC(50) of 80 nM. Compound 12p also shows good selectivity over MMP-1, -13, -14.
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==Function==
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Synthesis and activity of tryptophan sulfonamide derivatives as novel non-hydroxamate TNF-alpha converting enzyme (TACE) inhibitors.,Park K, Gopalsamy A, Aplasca A, Ellingboe JW, Xu W, Zhang Y, Levin JI Bioorg Med Chem. 2009 Jun 1;17(11):3857-65. Epub 2009 Apr 22. PMID:19410464<ref>PMID:19410464</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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[[3g42]] is a 4 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=3G42 OCA].
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</div>
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<div class="pdbe-citations 3g42" 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:019410464</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: Aplasca, A.]]
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[[Category: Large Structures]]
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[[Category: Gopalsamy, A.]]
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[[Category: Aplasca A]]
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[[Category: K., Park.]]
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[[Category: Gopalsamy A]]
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[[Category: Levin, J I.]]
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[[Category: Levin JI]]
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[[Category: Xu, W.]]
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[[Category: Park K]]
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[[Category: Zhang, Y H.]]
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[[Category: Xu W]]
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[[Category: Cleavage on pair of basic residue]]
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[[Category: Zhang YH]]
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[[Category: Glycoprotein]]
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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: Sh3-binding]]
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[[Category: Tace-inhibitor complex]]
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[[Category: Tace/adam-17]]
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[[Category: Transmembrane]]
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[[Category: Zn-endopeptidase]]
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[[Category: Zymogen]]
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Current revision

Crystal Structure of TACE with Tryptophan Sulfonamide Derivative Inhibitor

PDB ID 3g42

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