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| | ==Crystal Structure of NIK with 11-bromo-5,6,7,8-tetrahydropyrimido[4',5':3,4]cyclohepta[1,2-b]indol-2-amine (T28)== | | ==Crystal Structure of NIK with 11-bromo-5,6,7,8-tetrahydropyrimido[4',5':3,4]cyclohepta[1,2-b]indol-2-amine (T28)== |
| - | <StructureSection load='4idt' size='340' side='right' caption='[[4idt]], [[Resolution|resolution]] 2.40Å' scene=''> | + | <StructureSection load='4idt' size='340' side='right'caption='[[4idt]], [[Resolution|resolution]] 2.40Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4idt]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4IDT OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4IDT FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4idt]] 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=4IDT OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4IDT FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=T28:11-BROMO-5,6,7,8-TETRAHYDROPYRIMIDO[4,5 3,4]CYCLOHEPTA[1,2-B]INDOL-2-AMINE'>T28</scene></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=T28:11-BROMO-5,6,7,8-TETRAHYDROPYRIMIDO[4,5 3,4]CYCLOHEPTA[1,2-B]INDOL-2-AMINE'>T28</scene></td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4idv|4idv]]</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=4idt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4idt OCA], [https://pdbe.org/4idt PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4idt RCSB], [https://www.ebi.ac.uk/pdbsum/4idt PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4idt ProSAT]</span></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">MAP3K14, NIK ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
| + | |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Mitogen-activated_protein_kinase_kinase_kinase Mitogen-activated protein kinase kinase kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.25 2.7.11.25] </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=4idt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4idt OCA], [http://pdbe.org/4idt PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4idt RCSB], [http://www.ebi.ac.uk/pdbsum/4idt PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4idt ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/M3K14_HUMAN M3K14_HUMAN]] Lymphotoxin beta-activated kinase which seems to be exclusively involved in the activation of NF-kappa-B and its transcriptional activity. Promotes proteolytic processing of NFKB2/P100, which leads to activation of NF-kappa-B via the non-canonical pathway. Could act in a receptor-selective manner.<ref>PMID:15084608</ref> | + | [https://www.uniprot.org/uniprot/M3K14_HUMAN M3K14_HUMAN] Lymphotoxin beta-activated kinase which seems to be exclusively involved in the activation of NF-kappa-B and its transcriptional activity. Promotes proteolytic processing of NFKB2/P100, which leads to activation of NF-kappa-B via the non-canonical pathway. Could act in a receptor-selective manner.<ref>PMID:15084608</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Mitogen-activated protein kinase kinase kinase]] | + | [[Category: Large Structures]] |
| - | [[Category: Liu, J]] | + | [[Category: Liu J]] |
| - | [[Category: Sudom, A]] | + | [[Category: Sudom A]] |
| - | [[Category: Wang, Z]] | + | [[Category: Wang Z]] |
| - | [[Category: 2-aminopyrimidine]]
| + | |
| - | [[Category: Nik]]
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| - | [[Category: P100 processing]]
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| - | [[Category: Transferase-transferase inhibitor complex]]
| + | |
| Structural highlights
Function
M3K14_HUMAN Lymphotoxin beta-activated kinase which seems to be exclusively involved in the activation of NF-kappa-B and its transcriptional activity. Promotes proteolytic processing of NFKB2/P100, which leads to activation of NF-kappa-B via the non-canonical pathway. Could act in a receptor-selective manner.[1]
Publication Abstract from PubMed
The discovery, structure-based design, synthesis, and optimization of NIK inhibitors are described. Our work began with an HTS hit, imidazopyridinyl pyrimidinamine 1. We utilized homology modeling and conformational analysis to optimize the indole scaffold leading to the discovery of novel and potent conformationally constrained inhibitors such as compounds 25 and 28. Compounds 25 and 31 were co-crystallized with NIK kinase domain to provide structural insights.
Inhibiting NF-kappaB-inducing kinase (NIK): discovery, structure-based design, synthesis, structure-activity relationship, and co-crystal structures.,Li K, McGee LR, Fisher B, Sudom A, Liu J, Rubenstein SM, Anwer MK, Cushing TD, Shin Y, Ayres M, Lee F, Eksterowicz J, Faulder P, Waszkowycz B, Plotnikova O, Farrelly E, Xiao SH, Chen G, Wang Z Bioorg Med Chem Lett. 2013 Mar 1;23(5):1238-44. doi: 10.1016/j.bmcl.2013.01.012. , Epub 2013 Jan 11. PMID:23374866[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Liao G, Zhang M, Harhaj EW, Sun SC. Regulation of the NF-kappaB-inducing kinase by tumor necrosis factor receptor-associated factor 3-induced degradation. J Biol Chem. 2004 Jun 18;279(25):26243-50. Epub 2004 Apr 14. PMID:15084608 doi:10.1074/jbc.M403286200
- ↑ Li K, McGee LR, Fisher B, Sudom A, Liu J, Rubenstein SM, Anwer MK, Cushing TD, Shin Y, Ayres M, Lee F, Eksterowicz J, Faulder P, Waszkowycz B, Plotnikova O, Farrelly E, Xiao SH, Chen G, Wang Z. Inhibiting NF-kappaB-inducing kinase (NIK): discovery, structure-based design, synthesis, structure-activity relationship, and co-crystal structures. Bioorg Med Chem Lett. 2013 Mar 1;23(5):1238-44. doi: 10.1016/j.bmcl.2013.01.012. , Epub 2013 Jan 11. PMID:23374866 doi:http://dx.doi.org/10.1016/j.bmcl.2013.01.012
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