6sze

From Proteopedia

(Difference between revisions)

Current revision

RIP2 Kinase Catalytic Domain complex with 5-Amino-1-Phenylpyrazole-4-Carboxamide.

Structural highlights

6sze 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:	,
Activity:	Non-specific serine/threonine protein kinase, with EC number 2.7.11.1
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

Herein we report the discovery of pyrazolocarboxamides as novel, potent, and kinase selective inhibitors of receptor interacting protein 2 kinase (RIP2). Fragment based screening and design principles led to the identification of the inhibitor series, and X-ray crystallography was used to inform key structural changes. Through key substitutions about the N1 and C5 N positions on the pyrazole ring significant kinase selectivity and potency were achieved. Bridged bicyclic pyrazolocarboxamide 11 represents a selective and potent inhibitor of RIP2 and will allow for a more detailed investigation of RIP2 inhibition as a therapeutic target for autoinflammatory disorders.

Discovery of Pyrazolocarboxamides as Potent and Selective Receptor Interacting Protein 2 (RIP2) Kinase Inhibitors.,Haffner CD, Charnley AK, Aquino CJ, Casillas L, Convery MA, Cox JA, Elban MA, Goodwin NC, Gough PJ, Haile PA, Hughes TV, Knapp-Reed B, Kreatsoulas C, Lakdawala AS, Li H, Lian Y, Lipshutz D, Mehlmann JF, Ouellette M, Romano J, Shewchuk L, Shu A, Votta BJ, Zhou H, Bertin J, Marquis RW ACS Med Chem Lett. 2019 Oct 11;10(11):1518-1523. doi:, 10.1021/acsmedchemlett.9b00141. eCollection 2019 Nov 14. PMID:31749904^[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
↑ Haffner CD, Charnley AK, Aquino CJ, Casillas L, Convery MA, Cox JA, Elban MA, Goodwin NC, Gough PJ, Haile PA, Hughes TV, Knapp-Reed B, Kreatsoulas C, Lakdawala AS, Li H, Lian Y, Lipshutz D, Mehlmann JF, Ouellette M, Romano J, Shewchuk L, Shu A, Votta BJ, Zhou H, Bertin J, Marquis RW. Discovery of Pyrazolocarboxamides as Potent and Selective Receptor Interacting Protein 2 (RIP2) Kinase Inhibitors. ACS Med Chem Lett. 2019 Oct 11;10(11):1518-1523. doi:, 10.1021/acsmedchemlett.9b00141. eCollection 2019 Nov 14. PMID:31749904 doi:http://dx.doi.org/10.1021/acsmedchemlett.9b00141

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/6sze"

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 6sze is ON HOLD
+==RIP2 Kinase Catalytic Domain complex with 5-Amino-1-Phenylpyrazole-4-Carboxamide.==
+<StructureSection load='6sze' size='340' side='right'caption='[[6sze]], [[Resolution|resolution]] 2.94&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[6sze]] 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=6SZE OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6SZE 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=M2B:5-Amino-1-Phenylpyrazole-4-Carboxamide'>M2B</scene></td></tr>
+<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] </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=6sze FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6sze OCA], [http://pdbe.org/6sze PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6sze RCSB], [http://www.ebi.ac.uk/pdbsum/6sze PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6sze 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 ==
+Herein we report the discovery of pyrazolocarboxamides as novel, potent, and kinase selective inhibitors of receptor interacting protein 2 kinase (RIP2). Fragment based screening and design principles led to the identification of the inhibitor series, and X-ray crystallography was used to inform key structural changes. Through key substitutions about the N1 and C5 N positions on the pyrazole ring significant kinase selectivity and potency were achieved. Bridged bicyclic pyrazolocarboxamide 11 represents a selective and potent inhibitor of RIP2 and will allow for a more detailed investigation of RIP2 inhibition as a therapeutic target for autoinflammatory disorders.
-Authors: Convery, M.A., Charnley, A.K., Shewchuk, L.
+Discovery of Pyrazolocarboxamides as Potent and Selective Receptor Interacting Protein 2 (RIP2) Kinase Inhibitors.,Haffner CD, Charnley AK, Aquino CJ, Casillas L, Convery MA, Cox JA, Elban MA, Goodwin NC, Gough PJ, Haile PA, Hughes TV, Knapp-Reed B, Kreatsoulas C, Lakdawala AS, Li H, Lian Y, Lipshutz D, Mehlmann JF, Ouellette M, Romano J, Shewchuk L, Shu A, Votta BJ, Zhou H, Bertin J, Marquis RW ACS Med Chem Lett. 2019 Oct 11;10(11):1518-1523. doi:, 10.1021/acsmedchemlett.9b00141. eCollection 2019 Nov 14. PMID:31749904<ref>PMID:31749904</ref>
-Description: RIP2 Kinase Catalytic Domain complex with 5-Amino-1-Phenylpyrazole-4-Carboxamide.
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
-[[Category: Charnley, A.K]]
+<div class="pdbe-citations 6sze" style="background-color:#fffaf0;"></div>
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Human]]
+[[Category: Large Structures]]
+[[Category: Non-specific serine/threonine protein kinase]]
+[[Category: Charnley, A K]]
+[[Category: Convery, M A]]
 [[Category: Shewchuk, L]]
-[[Category: Convery, M.A]]
+[[Category: Receptor interacting protein 2 kinase]]
+[[Category: Rip2]]
+[[Category: Rip2k]]
+[[Category: Ripk2]]
+[[Category: Transferase]]

6sze

From Proteopedia

Current revision

RIP2 Kinase Catalytic Domain complex with 5-Amino-1-Phenylpyrazole-4-Carboxamide.

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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