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| | ==Crystal structure of catalytic domain of TACE with 2-(2-Aminothiazol-4-yl)pyrrolidine-Based Tartrate Diamides== | | ==Crystal structure of catalytic domain of TACE with 2-(2-Aminothiazol-4-yl)pyrrolidine-Based Tartrate Diamides== |
| - | <StructureSection load='3o64' size='340' side='right' caption='[[3o64]], [[Resolution|resolution]] 1.88Å' scene=''> | + | <StructureSection load='3o64' size='340' side='right'caption='[[3o64]], [[Resolution|resolution]] 1.88Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[3o64]] 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=3O64 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3O64 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[3o64]] 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=3O64 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3O64 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=786:(2R,3R)-2,3-DIHYDROXY-4-{(2R)-2-[2-(METHYLAMINO)-5-(METHYLSULFONYL)-1,3-THIAZOL-4-YL]PYRROLIDIN-1-YL}-4-OXO-N-{(1R)-1-[4-(1H-PYRAZOL-1-YL)PHENYL]ETHYL}BUTANAMIDE'>786</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=INN:N-{(2R)-2-[2-(HYDROXYAMINO)-2-OXOETHYL]-4-METHYLPENTANOYL}-3-METHYL-L-VALYL-N-(2-AMINOETHYL)-L-ALANINAMIDE'>INN</scene>, <scene name='pdbligand=IPA:ISOPROPYL+ALCOHOL'>IPA</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.88Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3lgp|3lgp]], [[3kmc|3kmc]], [[3kme|3kme]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=786:(2R,3R)-2,3-DIHYDROXY-4-{(2R)-2-[2-(METHYLAMINO)-5-(METHYLSULFONYL)-1,3-THIAZOL-4-YL]PYRROLIDIN-1-YL}-4-OXO-N-{(1R)-1-[4-(1H-PYRAZOL-1-YL)PHENYL]ETHYL}BUTANAMIDE'>786</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=INN:N-{(2R)-2-[2-(HYDROXYAMINO)-2-OXOETHYL]-4-METHYLPENTANOYL}-3-METHYL-L-VALYL-N-(2-AMINOETHYL)-L-ALANINAMIDE'>INN</scene>, <scene name='pdbligand=IPA:ISOPROPYL+ALCOHOL'>IPA</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> |
| - | <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>
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3o64 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3o64 OCA], [https://pdbe.org/3o64 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3o64 RCSB], [https://www.ebi.ac.uk/pdbsum/3o64 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3o64 ProSAT]</span></td></tr> |
| - | <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>
| + | |
| - | <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=3o64 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3o64 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3o64 RCSB], [http://www.ebi.ac.uk/pdbsum/3o64 PDBsum]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[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> | + | [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 == | | == Function == |
| - | [[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> | + | [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;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| | </div> | | </div> |
| | + | <div class="pdbe-citations 3o64" style="background-color:#fffaf0;"></div> |
| | | | |
| | ==See Also== | | ==See Also== |
| - | *[[A Disintegrin And Metalloproteinase|A Disintegrin And Metalloproteinase]] | + | *[[A Disintegrin And Metalloproteinase 3D structures|A Disintegrin And Metalloproteinase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: ADAM 17 endopeptidase]] | |
| | [[Category: Homo sapiens]] | | [[Category: Homo sapiens]] |
| - | [[Category: Orth, P]] | + | [[Category: Large Structures]] |
| - | [[Category: Adam protein]] | + | [[Category: Orth P]] |
| - | [[Category: Enzyme inhibitor]]
| + | |
| - | [[Category: Hydrolase]]
| + | |
| - | [[Category: Hydrolase-hydrolase inhibitor complex]]
| + | |
| Structural highlights
3o64 is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Method: | X-ray diffraction, Resolution 1.88Å |
| Ligands: | , , , , |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
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]
Publication Abstract from PubMed
TNF-alpha converting enzyme (TACE) inhibitors are promising agents to treat inflammatory disorders and cancer. We have investigated novel tartrate diamide TACE inhibitors where the tartrate core binds to zinc in a unique tridentate fashion. Incorporating (R)-2-(2-N-alkylaminothiazol-4-yl)pyrrolidines into the left hand side amide of the tartrate scaffold led to the discovery of potent and selective TACE inhibitors, some of which exhibited good rat oral bioavailability.
2-(2-Aminothiazol-4-yl)pyrrolidine-based tartrate diamides as potent, selective and orally bioavailable TACE inhibitors.,Dai C, Li D, Popovici-Muller J, Zhao L, Girijavallabhan VM, Rosner KE, Lavey BJ, Rizvi R, Shankar BB, Wong MK, Guo Z, Orth P, Strickland CO, Sun J, Niu X, Chen S, Kozlowski JA, Lundell DJ, Piwinski JJ, Shih NY, Siddiqui MA Bioorg Med Chem Lett. 2011 Jan 6. PMID:21458257[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ Dai C, Li D, Popovici-Muller J, Zhao L, Girijavallabhan VM, Rosner KE, Lavey BJ, Rizvi R, Shankar BB, Wong MK, Guo Z, Orth P, Strickland CO, Sun J, Niu X, Chen S, Kozlowski JA, Lundell DJ, Piwinski JJ, Shih NY, Siddiqui MA. 2-(2-Aminothiazol-4-yl)pyrrolidine-based tartrate diamides as potent, selective and orally bioavailable TACE inhibitors. Bioorg Med Chem Lett. 2011 Jan 6. PMID:21458257 doi:10.1016/j.bmcl.2011.01.002
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