6rn8

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Revision as of 06:27, 7 August 2019

RIP2 Kinase Catalytic Domain complex with 2(4[(1,3benzothiazol5yl)amino]6(2methylpropane2sulfonyl)quinazolin7yl)oxy)ethyl phosphate

Structural highlights

6rn8 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

RIP2 kinase has been identified as a key signal transduction partner in the NOD2 pathway contributing to a variety of human pathologies, including immune-mediated inflammatory diseases. Small-molecule inhibitors of RIP2 kinase or its signaling partners on the NOD2 pathway that are suitable for advancement into the clinic have yet to be described. Herein, we report our discovery and profile of the prodrug clinical compound, inhibitor 3, currently in phase 1 clinical studies. Compound 3 potently binds to RIP2 kinase with good kinase specificity and has excellent activity in blocking many proinflammatory cytokine responses in vivo and in human IBD explant samples. The highly favorable physicochemical and ADMET properties of 3 combined with high potency led to a predicted low oral dose in humans.

Discovery of a First-in-Class Receptor Interacting Protein 2 (RIP2) Kinase Specific Clinical Candidate, 2-((4-(Benzo[ d]thiazol-5-ylamino)-6-( tert-butylsulfonyl)quinazolin-7-yl)oxy)ethyl Dihydrogen Phosphate, for the Treatment of Inflammatory Diseases.,Haile PA, Casillas LN, Votta BJ, Wang GZ, Charnley AK, Dong X, Bury MJ, Romano JJ, Mehlmann JF, King BW, Erhard KF, Hanning CR, Lipshutz DB, Desai BM, Capriotti CA, Schaeffer MC, Berger SB, Mahajan MK, Reilly MA, Nagilla R, Rivera EJ, Sun HH, Kenna JK, Beal AM, Ouellette MT, Kelly M, Stemp G, Convery MA, Vossenkamper A, MacDonald TT, Gough PJ, Bertin J, Marquis RW J Med Chem. 2019 Jul 2. doi: 10.1021/acs.jmedchem.9b00575. PMID:31265286^[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
↑ Haile PA, Casillas LN, Votta BJ, Wang GZ, Charnley AK, Dong X, Bury MJ, Romano JJ, Mehlmann JF, King BW, Erhard KF, Hanning CR, Lipshutz DB, Desai BM, Capriotti CA, Schaeffer MC, Berger SB, Mahajan MK, Reilly MA, Nagilla R, Rivera EJ, Sun HH, Kenna JK, Beal AM, Ouellette MT, Kelly M, Stemp G, Convery MA, Vossenkamper A, MacDonald TT, Gough PJ, Bertin J, Marquis RW. Discovery of a First-in-Class Receptor Interacting Protein 2 (RIP2) Kinase Specific Clinical Candidate, 2-((4-(Benzo[ d]thiazol-5-ylamino)-6-( tert-butylsulfonyl)quinazolin-7-yl)oxy)ethyl Dihydrogen Phosphate, for the Treatment of Inflammatory Diseases. J Med Chem. 2019 Jul 2. doi: 10.1021/acs.jmedchem.9b00575. PMID:31265286 doi:http://dx.doi.org/10.1021/acs.jmedchem.9b00575

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/6rn8"

@@ Line 3: / Line 3: @@
 <StructureSection load='6rn8' size='340' side='right'caption='[[6rn8]], [[Resolution|resolution]] 2.69&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6rn8]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6RN8 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6RN8 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6rn8]] 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=6RN8 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6RN8 FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=K9T:2-[4-(1,3-benzothiazol-5-ylamino)-6-~{tert}-butylsulfonyl-quinazolin-7-yl]oxyethyl+dihydrogen+phosphate'>K9T</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=6rn8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6rn8 OCA], [http://pdbe.org/6rn8 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6rn8 RCSB], [http://www.ebi.ac.uk/pdbsum/6rn8 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6rn8 ProSAT]</span></td></tr>
 </table>
@@ Line 22: / Line 23: @@
 __TOC__
 </StructureSection>
+[[Category: Human]]
 [[Category: Large Structures]]
 [[Category: Convery, M A]]

6rn8

From Proteopedia

Revision as of 06:27, 7 August 2019

RIP2 Kinase Catalytic Domain complex with 2(4[(1,3benzothiazol5yl)amino]6(2methylpropane2sulfonyl)quinazolin7yl)oxy)ethyl phosphate

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

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