6oko

From Proteopedia

(Difference between revisions)

Revision as of 09:36, 1 April 2020

Crystal structure of mRIPK3 complexed with N-(3-fluoro-4-{1H-pyrrolo[2,3-b]pyridin-4-yloxy}phenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide

Structural highlights

6oko is a 2 chain structure with sequence from Lk3 transgenic mice. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Gene:	Ripk3, Rip3 (LK3 transgenic mice)
Activity:	Non-specific serine/threonine protein kinase, with EC number 2.7.11.1
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[RIPK3_MOUSE] Essential for programmed necrosis in response to death-inducing TNF-alpha family members. Upon induction of necrosis, RIPK3 interacts with, and phosphorylates RIPK1 to form a necrosis-inducing complex. RIPK3 binds to and enhances the activity of three metabolic enzymes: GLUL, GLUD1, and PYGL. These metabolic enzymes may eventually stimulate the tricarboxylic acid cycle and oxidative phosphorylation, which could result in enhanced ROS production (By similarity).^[1]

Publication Abstract from PubMed

Necroptosis has been implicated in a variety of disease states, and RIPK3 is one of the kinases identified to play a critical role in this signaling pathway. In an effort to identify RIPK3 kinase inhibitors with a novel profile, mechanistic studies were incorporated at the hit triage stage. Utilization of these assays enabled identification of a Type II DFG-out inhibitor for RIPK3, which was confirmed by protein crystallography. Structure-based drug design on the inhibitors targeting this previously unreported conformation enabled an enhancement in selectivity against key off-target kinases.

Identification of RIPK3 Type II Inhibitors Using High-Throughput Mechanistic Studies in Hit Triage.,Hart AC, Abell L, Guo J, Mertzman ME, Padmanabha R, Macor JE, Chaudhry C, Lu H, O'Malley K, Shaw PJ, Weigelt C, Pokross M, Kish K, Kim KS, Cornelius L, Douglas AE, Calambur D, Zhang P, Carpenter B, Pitts WJ ACS Med Chem Lett. 2019 May 6;11(3):266-271. doi: 10.1021/acsmedchemlett.9b00065., eCollection 2020 Mar 12. PMID:32184955^[2]

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

References

↑ Rebsamen M, Heinz LX, Meylan E, Michallet MC, Schroder K, Hofmann K, Vazquez J, Benedict CA, Tschopp J. DAI/ZBP1 recruits RIP1 and RIP3 through RIP homotypic interaction motifs to activate NF-kappaB. EMBO Rep. 2009 Aug;10(8):916-22. doi: 10.1038/embor.2009.109. Epub 2009 Jul 10. PMID:19590578 doi:http://dx.doi.org/10.1038/embor.2009.109
↑ Hart AC, Abell L, Guo J, Mertzman ME, Padmanabha R, Macor JE, Chaudhry C, Lu H, O'Malley K, Shaw PJ, Weigelt C, Pokross M, Kish K, Kim KS, Cornelius L, Douglas AE, Calambur D, Zhang P, Carpenter B, Pitts WJ. Identification of RIPK3 Type II Inhibitors Using High-Throughput Mechanistic Studies in Hit Triage. ACS Med Chem Lett. 2019 May 6;11(3):266-271. doi: 10.1021/acsmedchemlett.9b00065., eCollection 2020 Mar 12. PMID:32184955 doi:http://dx.doi.org/10.1021/acsmedchemlett.9b00065

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

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

@@ Line 3: / Line 3: @@
 <StructureSection load='6oko' size='340' side='right'caption='[[6oko]], [[Resolution|resolution]] 2.10&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6oko]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6OKO OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6OKO FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6oko]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Lk3_transgenic_mice Lk3 transgenic mice]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6OKO OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6OKO FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=1FN:1-(4-FLUOROPHENYL)-N-[3-FLUORO-4-(1H-PYRROLO[2,3-B]PYRIDIN-4-YLOXY)PHENYL]-2-OXO-1,2-DIHYDROPYRIDINE-3-CARBOXAMIDE'>1FN</scene></td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">Ripk3, Rip3 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10090 LK3 transgenic mice])</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=6oko FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6oko OCA], [http://pdbe.org/6oko PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6oko RCSB], [http://www.ebi.ac.uk/pdbsum/6oko PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6oko ProSAT]</span></td></tr>
@@ Line 10: / Line 11: @@
 == Function ==
 [[http://www.uniprot.org/uniprot/RIPK3_MOUSE RIPK3_MOUSE]] Essential for programmed necrosis in response to death-inducing TNF-alpha family members. Upon induction of necrosis, RIPK3 interacts with, and phosphorylates RIPK1 to form a necrosis-inducing complex. RIPK3 binds to and enhances the activity of three metabolic enzymes: GLUL, GLUD1, and PYGL. These metabolic enzymes may eventually stimulate the tricarboxylic acid cycle and oxidative phosphorylation, which could result in enhanced ROS production (By similarity).<ref>PMID:19590578</ref>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Necroptosis has been implicated in a variety of disease states, and RIPK3 is one of the kinases identified to play a critical role in this signaling pathway. In an effort to identify RIPK3 kinase inhibitors with a novel profile, mechanistic studies were incorporated at the hit triage stage. Utilization of these assays enabled identification of a Type II DFG-out inhibitor for RIPK3, which was confirmed by protein crystallography. Structure-based drug design on the inhibitors targeting this previously unreported conformation enabled an enhancement in selectivity against key off-target kinases.
+Identification of RIPK3 Type II Inhibitors Using High-Throughput Mechanistic Studies in Hit Triage.,Hart AC, Abell L, Guo J, Mertzman ME, Padmanabha R, Macor JE, Chaudhry C, Lu H, O'Malley K, Shaw PJ, Weigelt C, Pokross M, Kish K, Kim KS, Cornelius L, Douglas AE, Calambur D, Zhang P, Carpenter B, Pitts WJ ACS Med Chem Lett. 2019 May 6;11(3):266-271. doi: 10.1021/acsmedchemlett.9b00065., eCollection 2020 Mar 12. PMID:32184955<ref>PMID:32184955</ref>
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
+<div class="pdbe-citations 6oko" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Serine/threonine protein kinase 3D structures|Serine/threonine protein kinase 3D structures]]
 == References ==
 <references/>
@@ Line 15: / Line 28: @@
 </StructureSection>
 [[Category: Large Structures]]
+[[Category: Lk3 transgenic mice]]
 [[Category: Non-specific serine/threonine protein kinase]]
 [[Category: Pokross, M E]]

6oko

From Proteopedia

Revision as of 09:36, 1 April 2020

Crystal structure of mRIPK3 complexed with N-(3-fluoro-4-{1H-pyrrolo[2,3-b]pyridin-4-yloxy}phenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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