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5hx6

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Revision as of 08:35, 27 May 2020

Crystal structure of RIP1 kinase with a benzo[b][1,4]oxazepin-4-one

Structural highlights

5hx6 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

The recent discovery of the role of receptor interacting protein 1 (RIP1) kinase in tumor necrosis factor (TNF)-mediated inflammation has led to its emergence as a highly promising target for the treatment of multiple inflammatory diseases. We screened RIP1 against GSK's DNA-encoded small-molecule libraries and identified a novel highly potent benzoxazepinone inhibitor series. We demonstrate that this template possesses complete monokinase selectivity for RIP1 plus unique species selectivity for primate versus nonprimate RIP1. We elucidate the conformation of RIP1 bound to this benzoxazepinone inhibitor driving its high kinase selectivity and design specific mutations in murine RIP1 to restore potency to levels similar to primate RIP1. This series differentiates itself from known RIP1 inhibitors in combining high potency and kinase selectivity with good pharmacokinetic profiles in rodents. The favorable developability profile of this benzoxazepinone template, as exemplified by compound 14 (GSK'481), makes it an excellent starting point for further optimization into a RIP1 clinical candidate.

DNA-Encoded Library Screening Identifies Benzo[b][1,4]oxazepin-4-ones as Highly Potent and Monoselective Receptor Interacting Protein 1 Kinase Inhibitors.,Harris PA, King BW, Bandyopadhyay D, Berger SB, Campobasso N, Capriotti CA, Cox JA, Dare L, Dong X, Finger JN, Grady LC, Hoffman SJ, Jeong JU, Kang J, Kasparcova V, Lakdawala AS, Lehr R, McNulty DE, Nagilla R, Ouellette MT, Pao CS, Rendina AR, Schaeffer MC, Summerfield JD, Swift BA, Totoritis RD, Ward P, Zhang A, Zhang D, Marquis RW, Bertin J, Gough PJ J Med Chem. 2016 Feb 23. PMID:26854747^[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, King BW, Bandyopadhyay D, Berger SB, Campobasso N, Capriotti CA, Cox JA, Dare L, Dong X, Finger JN, Grady LC, Hoffman SJ, Jeong JU, Kang J, Kasparcova V, Lakdawala AS, Lehr R, McNulty DE, Nagilla R, Ouellette MT, Pao CS, Rendina AR, Schaeffer MC, Summerfield JD, Swift BA, Totoritis RD, Ward P, Zhang A, Zhang D, Marquis RW, Bertin J, Gough PJ. DNA-Encoded Library Screening Identifies Benzo[b][1,4]oxazepin-4-ones as Highly Potent and Monoselective Receptor Interacting Protein 1 Kinase Inhibitors. J Med Chem. 2016 Feb 23. PMID:26854747 doi:http://dx.doi.org/10.1021/acs.jmedchem.5b01898

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/5hx6"

@@ Line 1: / Line 1: @@
 ==Crystal structure of RIP1 kinase with a benzo[b][1,4]oxazepin-4-one==
-<StructureSection load='5hx6' size='340' side='right' caption='[[5hx6]], [[Resolution|resolution]] 2.23&Aring;' scene=''>
+<StructureSection load='5hx6' size='340' side='right'caption='[[5hx6]], [[Resolution|resolution]] 2.23&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5hx6]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5HX6 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5HX6 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5hx6]] 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=5HX6 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5HX6 FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=65U:5-BENZYL-N-[(3S)-5-METHYL-4-OXO-2,3,4,5-TETRAHYDRO-1,5-BENZOXAZEPIN-3-YL]-1,2-OXAZOLE-3-CARBOXAMIDE'>65U</scene></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=65U:5-BENZYL-N-[(3S)-5-METHYL-4-OXO-2,3,4,5-TETRAHYDRO-1,5-BENZOXAZEPIN-3-YL]-1,2-OXAZOLE-3-CARBOXAMIDE'>65U</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=5hx6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5hx6 OCA], [http://pdbe.org/5hx6 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5hx6 RCSB], [http://www.ebi.ac.uk/pdbsum/5hx6 PDBsum]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5hx6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5hx6 OCA], [http://pdbe.org/5hx6 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5hx6 RCSB], [http://www.ebi.ac.uk/pdbsum/5hx6 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5hx6 ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 23: / Line 24: @@
 __TOC__
 </StructureSection>
+[[Category: Human]]
+[[Category: Large Structures]]
 [[Category: Non-specific serine/threonine protein kinase]]
 [[Category: Campobasso, N]]

5hx6

From Proteopedia

Revision as of 08:35, 27 May 2020

Crystal structure of RIP1 kinase with a benzo[b][1,4]oxazepin-4-one

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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