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4neu

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Revision as of 21:13, 4 August 2016

X-ray structure of Receptor Interacting Protein 1 (RIP1)kinase domain with a 1-aminoisoquinoline inhibitor

Structural highlights

4neu 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:	RIPK1, RIP, RIP1 (HUMAN)
Activity:	Non-specific serine/threonine protein kinase, with EC number 2.7.11.1
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[RIPK1_HUMAN] Serine-threonine kinase which transduces inflammatory and cell-death signals (programmed necrosis) following death receptors ligation, activation of pathogen recognition receptors (PRRs), and DNA damage. Upon activation of TNFR1 by the TNF-alpha family cytokines, TRADD and TRAF2 are recruited to the receptor. Ubiquitination by TRAF2 via 'Lys-63'-link chains acts as a critical enhancer of communication with downstream signal transducers in the mitogen-activated protein kinase pathway and the NF-kappa-B pathway, which in turn mediate downstream events including the activation of genes encoding inflammatory molecules. Polyubiquitinated protein binds to IKBKG/NEMO, the regulatory subunit of the IKK complex, a critical event for NF-kappa-B activation. Interaction with other cellular RHIM-containing adapters initiates gene activation and cell death. RIPK1 and RIPK3 association, in particular, forms a necrosis-inducing complex.^[1] ^[2] ^[3]

Publication Abstract from PubMed

Potent inhibitors of RIP1 kinase from three distinct series, 1-aminoisoquinolines, pyrrolo[2,3-b]pyridines, and furo[2,3-d]pyrimidines, all of the type II class recognizing a DLG-out inactive conformation, were identified from screening of our in-house kinase focused sets. An exemplar from the furo[2,3-d]pyrimidine series showed a dose proportional response in protection from hypothermia in a mouse model of TNFalpha induced lethal shock.

Discovery of Small Molecule RIP1 Kinase Inhibitors for the Treatment of Pathologies Associated with Necroptosis.,Harris PA, Bandyopadhyay D, Berger SB, Campobasso N, Capriotti CA, Cox JA, Dare L, Finger JN, Hoffman SJ, Kahler KM, Lehr R, Lich JD, Nagilla R, Nolte RT, Ouellette MT, Pao CS, Schaeffer MC, Smallwood A, Sun HH, Swift BA, Totoritis RD, Ward P, Marquis RW, Bertin J, Gough PJ ACS Med Chem Lett. 2013 Nov 4;4(12):1238-43. doi: 10.1021/ml400382p. eCollection , 2013 Dec 12. PMID:24900635^[4]

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

References

↑ Holler N, Zaru R, Micheau O, Thome M, Attinger A, Valitutti S, Bodmer JL, Schneider P, Seed B, Tschopp J. Fas triggers an alternative, caspase-8-independent cell death pathway using the kinase RIP as effector molecule. Nat Immunol. 2000 Dec;1(6):489-95. PMID:11101870 doi:10.1038/82732
↑ Cho YS, Challa S, Moquin D, Genga R, Ray TD, Guildford M, Chan FK. Phosphorylation-driven assembly of the RIP1-RIP3 complex regulates programmed necrosis and virus-induced inflammation. Cell. 2009 Jun 12;137(6):1112-23. doi: 10.1016/j.cell.2009.05.037. PMID:19524513 doi:10.1016/j.cell.2009.05.037
↑ He S, Wang L, Miao L, Wang T, Du F, Zhao L, Wang X. Receptor interacting protein kinase-3 determines cellular necrotic response to TNF-alpha. Cell. 2009 Jun 12;137(6):1100-11. doi: 10.1016/j.cell.2009.05.021. PMID:19524512 doi:10.1016/j.cell.2009.05.021
↑ Harris PA, Bandyopadhyay D, Berger SB, Campobasso N, Capriotti CA, Cox JA, Dare L, Finger JN, Hoffman SJ, Kahler KM, Lehr R, Lich JD, Nagilla R, Nolte RT, Ouellette MT, Pao CS, Schaeffer MC, Smallwood A, Sun HH, Swift BA, Totoritis RD, Ward P, Marquis RW, Bertin J, Gough PJ. Discovery of Small Molecule RIP1 Kinase Inhibitors for the Treatment of Pathologies Associated with Necroptosis. ACS Med Chem Lett. 2013 Nov 4;4(12):1238-43. doi: 10.1021/ml400382p. eCollection , 2013 Dec 12. PMID:24900635 doi:http://dx.doi.org/10.1021/ml400382p

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/4neu"

@@ Line 1: / Line 1: @@
 ==X-ray structure of Receptor Interacting Protein 1 (RIP1)kinase domain with a 1-aminoisoquinoline inhibitor==
 <StructureSection load='4neu' size='340' side='right' caption='[[4neu]], [[Resolution|resolution]] 2.57&Aring;' scene=''>
@@ Line 6: / Line 7: @@
 <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">RIPK1, RIP, RIP1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=4neu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4neu OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4neu RCSB], [http://www.ebi.ac.uk/pdbsum/4neu PDBsum]</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=4neu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4neu OCA], [http://pdbe.org/4neu PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4neu RCSB], [http://www.ebi.ac.uk/pdbsum/4neu PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4neu ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 18: / Line 19: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 4neu" style="background-color:#fffaf0;"></div>
 == References ==
 <references/>

4neu

From Proteopedia

Revision as of 21:13, 4 August 2016

X-ray structure of Receptor Interacting Protein 1 (RIP1)kinase domain with a 1-aminoisoquinoline inhibitor

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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