6ul8: Difference between revisions
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<StructureSection load='6ul8' size='340' side='right'caption='[[6ul8]], [[Resolution|resolution]] 2.68Å' scene=''> | <StructureSection load='6ul8' size='340' side='right'caption='[[6ul8]], [[Resolution|resolution]] 2.68Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[6ul8]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6UL8 OCA]. For a <b>guided tour on the structure components</b> use [ | <table><tr><td colspan='2'>[[6ul8]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6UL8 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6UL8 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=Q9J:(5S,6S,8R)-2-(1,3-benzothiazol-5-yl)-6-hydroxy-4,5,6,7,8,9-hexahydro-5,8-methanopyrazolo[1,5-a][1,3]diazocine-3-carboxamide'>Q9J</scene></td></tr> | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.68Å</td></tr> | ||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=Q9J:(5S,6S,8R)-2-(1,3-benzothiazol-5-yl)-6-hydroxy-4,5,6,7,8,9-hexahydro-5,8-methanopyrazolo[1,5-a][1,3]diazocine-3-carboxamide'>Q9J</scene></td></tr> | ||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6ul8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ul8 OCA], [https://pdbe.org/6ul8 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6ul8 RCSB], [https://www.ebi.ac.uk/pdbsum/6ul8 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6ul8 ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Function == | == Function == | ||
[ | [https://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;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
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</div> | </div> | ||
<div class="pdbe-citations 6ul8" style="background-color:#fffaf0;"></div> | <div class="pdbe-citations 6ul8" style="background-color:#fffaf0;"></div> | ||
==See Also== | |||
*[[Serine/threonine protein kinase 3D structures|Serine/threonine protein kinase 3D structures]] | |||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Convery | [[Category: Convery MA]] | ||
[[Category: Shewchuk | [[Category: Shewchuk LM]] | ||
Latest revision as of 10:53, 11 October 2023
RIP2 kinase catalytic domain complex with (5S,6S,8R)-2-(benzo[d]thiazol-5-yl)-6-hydroxy-4,5,6,7,8,9-hexahydro-5,8-methanopyrazolo[1,5-a][1,3]diazocine-3-carboxamideRIP2 kinase catalytic domain complex with (5S,6S,8R)-2-(benzo[d]thiazol-5-yl)-6-hydroxy-4,5,6,7,8,9-hexahydro-5,8-methanopyrazolo[1,5-a][1,3]diazocine-3-carboxamide
Structural highlights
FunctionRIPK2_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 PubMedHerein 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. See AlsoReferences
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