3le9: Difference between revisions
New page: '''Unreleased structure''' The entry 3le9 is ON HOLD until Paper Publication Authors: Orth, P. Description: Crystal structure of the catalytic domain of TACE with Indazolinone-phenyl-h... |
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The | ==Crystal structure of the catalytic domain of TACE with Indazolinone-phenyl-hydantoin inhibitor== | ||
<StructureSection load='3le9' size='340' side='right'caption='[[3le9]], [[Resolution|resolution]] 1.85Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[3le9]] 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=3LE9 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3LE9 FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.85Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=727:(5R)-5-[(5-METHOXY-3-OXO-1,3-DIHYDRO-2H-INDAZOL-2-YL)METHYL]-5-PHENYLIMIDAZOLIDINE-2,4-DIONE'>727</scene>, <scene name='pdbligand=IPA:ISOPROPYL+ALCOHOL'>IPA</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3le9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3le9 OCA], [https://pdbe.org/3le9 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3le9 RCSB], [https://www.ebi.ac.uk/pdbsum/3le9 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3le9 ProSAT]</span></td></tr> | |||
</table> | |||
== Disease == | |||
[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> | |||
== Function == | |||
[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> | |||
<div style="background-color:#fffaf0;"> | |||
== 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<ref>PMID:20663669</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 3le9" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[A Disintegrin And Metalloproteinase 3D structures|A Disintegrin And Metalloproteinase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Orth P]] | |||
Latest revision as of 09:35, 19 July 2023
Crystal structure of the catalytic domain of TACE with Indazolinone-phenyl-hydantoin inhibitorCrystal structure of the catalytic domain of TACE with Indazolinone-phenyl-hydantoin inhibitor
Structural highlights
DiseaseADA17_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] FunctionADA17_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] Publication Abstract from PubMedWe 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[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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