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| <StructureSection load='6ocq' size='340' side='right'caption='[[6ocq]], [[Resolution|resolution]] 2.79Å' scene=''> | | <StructureSection load='6ocq' size='340' side='right'caption='[[6ocq]], [[Resolution|resolution]] 2.79Å' scene=''> |
| == Structural highlights == | | == Structural highlights == |
| <table><tr><td colspan='2'>[[6ocq]] 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=6OCQ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6OCQ FirstGlance]. <br> | | <table><tr><td colspan='2'>[[6ocq]] 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=6OCQ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6OCQ FirstGlance]. <br> |
| </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=M5J:1-[(2S)-2-(3-fluorophenyl)pyrrolidin-1-yl]-2,2-dimethylpropan-1-one'>M5J</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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]] 2.793Å</td></tr> |
| <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[6r5f|6r5f]]</td></tr>
| | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=M5J:1-[(2S)-2-(3-fluorophenyl)pyrrolidin-1-yl]-2,2-dimethylpropan-1-one'>M5J</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6ocq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ocq OCA], [https://pdbe.org/6ocq PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6ocq RCSB], [https://www.ebi.ac.uk/pdbsum/6ocq PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6ocq ProSAT]</span></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=6ocq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ocq OCA], [http://pdbe.org/6ocq PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6ocq RCSB], [http://www.ebi.ac.uk/pdbsum/6ocq PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6ocq ProSAT]</span></td></tr> | |
| </table> | | </table> |
| == Function == | | == Function == |
| [[http://www.uniprot.org/uniprot/RIPK1_HUMAN 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.<ref>PMID:11101870</ref> <ref>PMID:19524513</ref> <ref>PMID:19524512</ref> | | [https://www.uniprot.org/uniprot/RIPK1_HUMAN 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.<ref>PMID:11101870</ref> <ref>PMID:19524513</ref> <ref>PMID:19524512</ref> |
| <div style="background-color:#fffaf0;">
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| == Publication Abstract from PubMed ==
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| RIP1 kinase regulates necroptosis and inflammation and may play an important role in contributing to a variety of human pathologies, including inflammatory and neurological diseases. Currently RIP1 kinase inhibitors have advanced into early clinical trials for evaluation in inflammatory diseases such as psoriasis, rheumatoid arthritis and ulcerative colitis, and neuro-logical diseases such as amyotrophic lateral sclerosis (ALS) and Alzheimer's disease. In this paper we report on the design of potent and highly selective dihydropyrazole (DHP) RIP1 kinase inhibitors starting from a high-throughput screen and the lead-optimization of this series from a lead with minimal rat oral exposure to the identification of dihydropyrazole 77 with good pharmacokinetic profiles in multiple species. Additionally, we identified a potent murine RIP1 kinase inhibitor 76 as a valuable in vivo tool molecule suitable for evaluating the role of RIP1 kinase in chronic models of disease. DHP 76 showed efficacy in mouse models of both multiple sclerosis and human retinitis pigmentosa.
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| Discovery and Lead-optimization of 4,5-Dihydropyrazoles as Mono-Kinase Selective, Orally Bioavailable and Efficacious Inhibitors of Receptor Interacting Protein 1 (RIP1) Kinase.,Harris PA, Faucher N, George N, Eidam PM, King BW, White G, Anderson NA, Bandyopadhyay D, Beal AM, Beneton V, Berger SB, Campobasso N, Campos S, Capriotti CA, Cox JA, Daugan A, Donche F, Fouchet MH, Finger JN, Geddes B, Gough PJ, Grondin P, Hoffman B, Hoffman SJ, Hutchinson S, Jeong JU, Jigorel E, Lamoureux P, Leister LK, Lich JD, Mahajan MK, Meslamani J, Mosley JE, Nagilla R, Nassau P, Ng SL, Ouellette MT, Pasikanti K, Potvain F, Reilly MA, Rivera EJ, Sautet S, Schaeffer MC, Sehon CA, Sun HH, Thorpe JH, Totoritis RD, Ward P, Wellaway N, Wisnoski DD, Woolven JM, Bertin J, Marquis RW J Med Chem. 2019 Apr 23. doi: 10.1021/acs.jmedchem.9b00318. PMID:31013427<ref>PMID:31013427</ref>
| | ==See Also== |
| | | *[[Serine/threonine protein kinase 3D structures|Serine/threonine protein kinase 3D structures]] |
| From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
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| </div>
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| <div class="pdbe-citations 6ocq" style="background-color:#fffaf0;"></div>
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| == References == | | == References == |
| <references/> | | <references/> |
| __TOC__ | | __TOC__ |
| </StructureSection> | | </StructureSection> |
| [[Category: Human]] | | [[Category: Homo sapiens]] |
| [[Category: Large Structures]] | | [[Category: Large Structures]] |
| [[Category: Non-specific serine/threonine protein kinase]]
| | [[Category: Harris PA]] |
| [[Category: Harris, P A]] | | [[Category: Thorpe JH]] |
| [[Category: Thorpe, J H]] | |
| [[Category: Inhibitor]]
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| [[Category: Signaling protein]]
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| [[Category: Signaling protein-inhibitor complex]]
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