6fu5
From Proteopedia
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(New page: '''Unreleased structure''' The entry 6fu5 is ON HOLD Authors: Pinkas, D.M., Bufton, J.C., Kupinska, K., Burgess-Brown, N.A., von Delft, F., Arrowsmith, C.H., Edwards, A.M., Bountra, C.,...) |
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| - | '''Unreleased structure''' | ||
| - | + | ==Structure of the kinase domain of human RIPK2 in complex with the inhibitor CSLP18== | |
| + | <StructureSection load='6fu5' size='340' side='right' caption='[[6fu5]], [[Resolution|resolution]] 3.26Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[6fu5]] 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=6FU5 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6FU5 FirstGlance]. <br> | ||
| + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=E7N:~{N}-[5-[2-azanyl-5-(4-piperazin-1-ylphenyl)pyridin-3-yl]-2-methoxy-phenyl]propane-1-sulfonamide'>E7N</scene></td></tr> | ||
| + | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">RIPK2, CARDIAK, RICK, RIP2, UNQ277/PRO314/PRO34092 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=6fu5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6fu5 OCA], [http://pdbe.org/6fu5 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6fu5 RCSB], [http://www.ebi.ac.uk/pdbsum/6fu5 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6fu5 ProSAT]</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 == | ||
| + | RIPK2 mediates inflammatory signaling by the bacteria-sensing receptors NOD1 and NOD2. Kinase inhibitors targeting RIPK2 are a proposed strategy to ameliorate NOD-mediated pathologies. Here, we reveal that RIPK2 kinase activity is dispensable for NOD2 inflammatory signaling and show that RIPK2 inhibitors function instead by antagonizing XIAP-binding and XIAP-mediated ubiquitination of RIPK2. We map the XIAP binding site on RIPK2 to the loop between beta2 and beta3 of the N-lobe of the kinase, which is in close proximity to the ATP-binding pocket. Through characterization of a new series of ATP pocket-binding RIPK2 inhibitors, we identify the molecular features that determine their inhibition of both the RIPK2-XIAP interaction, and of cellular and in vivoNOD2 signaling. Our study exemplifies how targeting of the ATP-binding pocket in RIPK2 can be exploited to interfere with the RIPK2-XIAP interaction for modulation of NOD signaling. | ||
| - | + | Small molecule inhibitors reveal an indispensable scaffolding role of RIPK2 in NOD2 signaling.,Hrdinka M, Schlicher L, Dai B, Pinkas DM, Bufton JC, Picaud S, Ward JA, Rogers C, Suebsuwong C, Nikhar S, Cuny GD, Huber KV, Filippakopoulos P, Bullock AN, Degterev A, Gyrd-Hansen M EMBO J. 2018 Jul 19. pii: embj.201899372. doi: 10.15252/embj.201899372. PMID:30026309<ref>PMID:30026309</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | + | </div> | |
| - | + | <div class="pdbe-citations 6fu5" style="background-color:#fffaf0;"></div> | |
| - | + | == References == | |
| - | + | <references/> | |
| - | + | __TOC__ | |
| - | + | </StructureSection> | |
| - | [[Category: | + | [[Category: Human]] |
| - | [[Category: | + | [[Category: Arrowsmith, C H]] |
[[Category: Bountra, C]] | [[Category: Bountra, C]] | ||
| + | [[Category: Bufton, J C]] | ||
| + | [[Category: Bullock, A N]] | ||
| + | [[Category: Burgess-Brown, N A]] | ||
| + | [[Category: Delft, F von]] | ||
| + | [[Category: Edwards, A M]] | ||
[[Category: Kupinska, K]] | [[Category: Kupinska, K]] | ||
| + | [[Category: Pinkas, D M]] | ||
| + | [[Category: Transferase]] | ||
Current revision
Structure of the kinase domain of human RIPK2 in complex with the inhibitor CSLP18
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