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6nw2

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Revision as of 08:22, 21 May 2019

Structure of human RIPK1 kinase domain in complex with compound 11

Structural highlights

6nw2 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

Receptor-interacting protein kinase 1 (RIPK1), a key component of the cellular necroptosis pathway, has gained recognition as an important therapeutic target. Pharmacologic inhibition or genetic inactivation of RIPK1 has shown promise in animal models of disease ranging from acute ischemic conditions, chronic inflammation, and neurodegeneration. We present here a class of RIPK1 inhibitors that is distinguished by a lack of a lipophilic aromatic group present in most literature inhibitors that typically occupies a hydrophobic back pocket of the protein active site. Despite not having this ubiquitous feature of many known RIPK1 inhibitors, we were able to obtain compounds with good potency, kinase selectivity, and pharmacokinetic properties in rats. The use of the lipophilic yet metabolically stable pentafluoroethyl group was critical to balancing the potency and properties of optimized analogs.

Potent and selective inhibitors of receptor-interacting protein kinase 1 that lack an aromatic back pocket group.,Hamilton GL, Chen H, Deshmukh G, Eigenbrot C, Fong R, Johnson A, Kohli PB, Lupardus PJ, Liederer BM, Ramaswamy S, Wang H, Wang J, Xu Z, Zhu Y, Vucic D, Patel S Bioorg Med Chem Lett. 2019 Apr 11. pii: S0960-894X(19)30223-9. doi:, 10.1016/j.bmcl.2019.04.014. PMID:31000154^[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
↑ Hamilton GL, Chen H, Deshmukh G, Eigenbrot C, Fong R, Johnson A, Kohli PB, Lupardus PJ, Liederer BM, Ramaswamy S, Wang H, Wang J, Xu Z, Zhu Y, Vucic D, Patel S. Potent and selective inhibitors of receptor-interacting protein kinase 1 that lack an aromatic back pocket group. Bioorg Med Chem Lett. 2019 Apr 11. pii: S0960-894X(19)30223-9. doi:, 10.1016/j.bmcl.2019.04.014. PMID:31000154 doi:http://dx.doi.org/10.1016/j.bmcl.2019.04.014

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/6nw2"

@@ Line 3: / Line 3: @@
 <StructureSection load='6nw2' size='340' side='right'caption='[[6nw2]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6nw2]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6NW2 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6NW2 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6nw2]] 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=6NW2 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6NW2 FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=L4Y:(5R)-5-methyl-N-[(3S)-5-methyl-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepin-3-yl]-4,5,6,7-tetrahydro-2H-indazole-3-carboxamide'>L4Y</scene></td></tr>
+<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=6nw2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6nw2 OCA], [http://pdbe.org/6nw2 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6nw2 RCSB], [http://www.ebi.ac.uk/pdbsum/6nw2 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6nw2 ProSAT]</span></td></tr>
@@ Line 23: / Line 24: @@
 __TOC__
 </StructureSection>
+[[Category: Human]]
 [[Category: Large Structures]]
 [[Category: Non-specific serine/threonine protein kinase]]

6nw2

From Proteopedia

Revision as of 08:22, 21 May 2019

Structure of human RIPK1 kinase domain in complex with compound 11

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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