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6es0

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Crystal structure of the kinase domain of human RIPK2 in complex with the activation loop targeting inhibitor CS-R35

Structural highlights

6es0 is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Gene:	RIPK2, CARDIAK, RICK, RIP2, UNQ277/PRO314/PRO34092 (HUMAN)
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[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.^[1] ^[2] ^[3] ^[4]

Publication Abstract from PubMed

Development of selective kinase inhibitors remains a challenge due to considerable amino acid sequence similarity among family members particularly in the ATP binding site. Targeting the activation loop might offer improved inhibitor selectivity since this region of kinases is less conserved. However, the strategy presents difficulties due to activation loop flexibility. Herein, we report the design of receptor-interacting protein kinase 2 (RIPK2) inhibitors based on pan-kinase inhibitor regorafenib that aim to engage basic activation loop residues Lys169 or Arg171. We report development of CSR35 that displayed >10-fold selective inhibition of RIPK2 versus VEGFR2, the target of regorafenib. A co-crystal structure of CSR35 with RIPK2 revealed a resolved activation loop with an ionic interaction between the carboxylic acid installed in the inhibitor and the side-chain of Lys169. Our data provides principle feasibility of developing activation loop targeting type II inhibitors as a complementary strategy for achieving improved selectivity.

Activation loop targeting strategy for design of receptor-interacting protein kinase 2 (RIPK2) inhibitors.,Suebsuwong C, Pinkas DM, Ray SS, Bufton JC, Dai B, Bullock AN, Degterev A, Cuny GD Bioorg Med Chem Lett. 2018 Feb 15;28(4):577-583. doi: 10.1016/j.bmcl.2018.01.044., Epub 2018 Jan 31. PMID:29409752^[5]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Ruefli-Brasse AA, Lee WP, Hurst S, Dixit VM. Rip2 participates in Bcl10 signaling and T-cell receptor-mediated NF-kappaB activation. J Biol Chem. 2004 Jan 9;279(2):1570-4. Epub 2003 Nov 24. PMID:14638696 doi:http://dx.doi.org/10.1074/jbc.C300460200
↑ Manon F, Favier A, Nunez G, Simorre JP, Cusack S. Solution structure of NOD1 CARD and mutational analysis of its interaction with the CARD of downstream kinase RICK. J Mol Biol. 2007 Jan 5;365(1):160-74. Epub 2006 Sep 29. PMID:17054981 doi:10.1016/j.jmb.2006.09.067
↑ Hasegawa M, Fujimoto Y, Lucas PC, Nakano H, Fukase K, Nunez G, Inohara N. A critical role of RICK/RIP2 polyubiquitination in Nod-induced NF-kappaB activation. EMBO J. 2008 Jan 23;27(2):373-83. Epub 2007 Dec 13. PMID:18079694 doi:http://dx.doi.org/10.1038/sj.emboj.7601962
↑ Tigno-Aranjuez JT, Asara JM, Abbott DW. Inhibition of RIP2's tyrosine kinase activity limits NOD2-driven cytokine responses. Genes Dev. 2010 Dec 1;24(23):2666-77. doi: 10.1101/gad.1964410. PMID:21123652 doi:http://dx.doi.org/10.1101/gad.1964410
↑ Suebsuwong C, Pinkas DM, Ray SS, Bufton JC, Dai B, Bullock AN, Degterev A, Cuny GD. Activation loop targeting strategy for design of receptor-interacting protein kinase 2 (RIPK2) inhibitors. Bioorg Med Chem Lett. 2018 Feb 15;28(4):577-583. doi: 10.1016/j.bmcl.2018.01.044., Epub 2018 Jan 31. PMID:29409752 doi:http://dx.doi.org/10.1016/j.bmcl.2018.01.044

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6es0"

@@ Line 1: / Line 1: @@
 ==Crystal structure of the kinase domain of human RIPK2 in complex with the activation loop targeting inhibitor CS-R35==
-<StructureSection load='6es0' size='340' side='right' caption='[[6es0]], [[Resolution|resolution]] 2.38&Aring;' scene=''>
+<StructureSection load='6es0' size='340' side='right'caption='[[6es0]], [[Resolution|resolution]] 2.38&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6es0]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6ES0 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6ES0 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6es0]] 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=6ES0 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6ES0 FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=BW8:2-[2-fluoranyl-4-[[2-fluoranyl-4-[2-(methylcarbamoyl)pyridin-4-yl]oxy-phenyl]carbamoylamino]phenyl]sulfanylethanoic+acid'>BW8</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=6es0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6es0 OCA], [http://pdbe.org/6es0 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6es0 RCSB], [http://www.ebi.ac.uk/pdbsum/6es0 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6es0 ProSAT]</span></td></tr>
 </table>
@@ Line 22: / Line 23: @@
 __TOC__
 </StructureSection>
+[[Category: Human]]
+[[Category: Large Structures]]
 [[Category: Arrowsmith, C H]]
 [[Category: Bountra, C]]

6es0

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Current revision

Crystal structure of the kinase domain of human RIPK2 in complex with the activation loop targeting inhibitor CS-R35

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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