5j7b
From Proteopedia
(Difference between revisions)
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| - | '''Unreleased structure''' | ||
| - | The | + | ==The identification and pharmacological characterization of 6-(tert-butylsulfonyl)-N-(5-fluoro-1H-indazol-3-yl)quinolin-4-amine (GSK583), a highly potent and selective inhibitor of RIP2 Kinase, GSK583 complex== |
| + | <StructureSection load='5j7b' size='340' side='right' caption='[[5j7b]], [[Resolution|resolution]] 2.53Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[5j7b]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5J7B OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5J7B FirstGlance]. <br> | ||
| + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=6GD:6-(TERT-BUTYLSULFONYL)-N-(5-FLUORO-2H-INDAZOL-3-YL)QUINOLIN-4-AMINE'>6GD</scene></td></tr> | ||
| + | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5j79|5j79]]</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=5j7b FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5j7b OCA], [http://pdbe.org/5j7b PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5j7b RCSB], [http://www.ebi.ac.uk/pdbsum/5j7b PDBsum]</span></td></tr> | ||
| + | </table> | ||
| + | == Function == | ||
| + | [[http://www.uniprot.org/uniprot/RIPK2_HUMAN RIPK2_HUMAN]] Serine/threonine/tyrosine kinase that plays an essential role in modulation of innate and adaptive immune responses. Upon stimulation by bacterial peptidoglycans, NOD1 and NOD2 are activated, oligomerize and recruit RIPK2 through CARD-CARD domains. Once recruited, RIPK2 autophosphorylates and undergoes 'Lys-63'-linked polyubiquitination by E3 ubiquitin ligases BIRC2 and BIRC3. The polyubiquitinated protein mediates the recruitment of MAP3K7/TAK1 to IKBKG/NEMO and induces 'Lys-63'-linked polyubiquitination of IKBKG/NEMO and subsequent activation of IKBKB/IKKB. In turn, NF-kappa-B is released from NF-kappa-B inhibitors and translocates into the nucleus where it activates the transcription of hundreds of genes involved in immune response, growth control, or protection against apoptosis. Plays also a role during engagement of the T-cell receptor (TCR) in promoting BCL10 phosphorylation and subsequent NF-kappa-B activation.<ref>PMID:14638696</ref> <ref>PMID:17054981</ref> <ref>PMID:18079694</ref> <ref>PMID:21123652</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | RIP2 kinase is a central component of the innate immune system and enables downstream signaling following activation of the pattern recognition receptors NOD1 and NOD2, leading to the production of inflammatory cytokines. Recently, several inhibitors of RIP2 kinase have been disclosed that have contributed to the fundamental understanding of the role of RIP2 in this pathway. However, because they lack either broad kinase selectivity or strong affinity for RIP2, these tools have only limited utility to assess the role of RIP2 in complex environments. We present, herein, the discovery and pharmacological characterization of GSK583, a next-generation RIP2 inhibitor possessing exquisite selectivity and potency. Having demonstrated the pharmacological precision of this tool compound, we report its use in elucidating the role of RIP2 kinase in a variety of in vitro, in vivo, and ex vivo experiments, further clarifying our understanding of the role of RIP2 in NOD1 and NOD2 mediated disease pathogenesis. | ||
| - | + | The Identification and Pharmacological Characterization of 6-(tert-Butylsulfonyl)-N-(5-fluoro-1H-indazol-3-yl)quinolin-4-amine (GSK583), a Highly Potent and Selective Inhibitor of RIP2 Kinase.,Haile PA, Votta BJ, Marquis RW, Bury MJ, Mehlmann JF, Singhaus R Jr, Charnley AK, Lakdawala AS, Convery MA, Lipshutz DB, Desai BM, Swift B, Capriotti CA, Berger SB, Mahajan MK, Reilly MA, Rivera EJ, Sun HH, Nagilla R, Beal AM, Finger JN, Cook MN, King BW, Ouellette MT, Totoritis RD, Pierdomenico M, Negroni A, Stronati L, Cucchiara S, Ziolkowski B, Vossenkamper A, MacDonald TT, Gough PJ, Bertin J, Casillas LN J Med Chem. 2016 May 26;59(10):4867-80. doi: 10.1021/acs.jmedchem.6b00211. Epub, 2016 May 4. PMID:27109867<ref>PMID:27109867</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| - | [[Category: Lakdawala, A | + | <div class="pdbe-citations 5j7b" style="background-color:#fffaf0;"></div> |
| - | [[Category: Votta, B | + | == References == |
| - | [[Category: | + | <references/> |
| - | [[Category: | + | __TOC__ |
| - | [[Category: | + | </StructureSection> |
| + | [[Category: Casillas, L N]] | ||
| + | [[Category: Convery, M A]] | ||
| + | [[Category: Haile, P A]] | ||
| + | [[Category: Lakdawala, A S]] | ||
| + | [[Category: Votta, B J]] | ||
| + | [[Category: Inhibitor selectivity]] | ||
| + | [[Category: Kinase domain]] | ||
| + | [[Category: Kinase inhibitor]] | ||
| + | [[Category: Structure-based drug design]] | ||
| + | [[Category: Transferase-transferase inhibitor complex]] | ||
Revision as of 15:57, 1 June 2016
The identification and pharmacological characterization of 6-(tert-butylsulfonyl)-N-(5-fluoro-1H-indazol-3-yl)quinolin-4-amine (GSK583), a highly potent and selective inhibitor of RIP2 Kinase, GSK583 complex
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