receptor interacting serine/threonine kinase 1

Target id: 2189

Nomenclature: receptor interacting serine/threonine kinase 1

Abbreviated Name: RIPK1

Family: Receptor interacting protein kinase (RIPK) family

Annotation status:  image of an orange circle Annotated and awaiting review. Please contact us if you can help with reviewing.  » Email us

   GtoImmuPdb view: OFF :     receptor interacting serine/threonine kinase 1 has curated GtoImmuPdb data

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 671 6p25.2 RIPK1 receptor interacting serine/threonine kinase 1
Mouse - 656 13 A3.3 Ripk1 receptor (TNFRSF)-interacting serine-threonine kinase 1
Rat - 658 17 p12 Ripk1 receptor interacting serine/threonine kinase 1
Previous and Unofficial Names
RIP | Rip1 | receptor (TNFRSF)-interacting serine-threonine kinase 1
Database Links
BRENDA
Ensembl Gene
Entrez Gene
GenitoUrinary Development Molecular Anatomy Project
Human Protein Atlas
KEGG Enzyme
KEGG Gene
OMIM
RefSeq Nucleotide
RefSeq Protein
SynPHARM
UniProtKB
Wikipedia
Selected 3D Structures
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of RIP1 kinase in complex with necrostatin-4
PDB Id:  4ITJ
Resolution:  1.8Å
Species:  Human
References:  13
Image of receptor 3D structure from RCSB PDB
Description:  X-ray structure of Receptor Interacting Protein 1 (RIP1)kinase domain with a 1-aminoisoquinoline inhibitor
PDB Id:  4NEU
Resolution:  2.57Å
Species:  Human
References:  5
Enzyme Reaction
EC Number: 2.7.11.1

Download all structure-activity data for this target as a CSV file

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
necrostatin-1s Hs Inhibition 7.4 pKd 3
pKd 7.4 (Kd 3.7x10-8 M) [3]
Description: Affinity constant measured at 37oC.
6E11 Hs Inhibition 6.4 pKd 4
pKd 6.4 (Kd 4x10-7 M) [4]
Description: Binding constant measured at 37oC.
GSK2982772 Hs Inhibition 9.0 pIC50 6
pIC50 9.0 (IC50 1x10-9 M) [6]
compound 21 [PMID: 24900635] Hs Inhibition 8.9 pIC50 5
pIC50 8.9 (IC50 1.3x10-9 M) [5]
RIPA-56 Hs Inhibition 7.9 pIC50 8
pIC50 7.9 (IC50 1.3x10-8 M) [8]
Description: Inhibition of RIPK1 activity in vitro.
necrostatin-1 Hs Inhibition 6.3 pIC50 2
pIC50 6.3 (IC50 4.9x10-7 M) [2]
Description: Measuring inhibition of cellular necrosis in TNFα-treated FADD-deficient Jurkat cells.
DiscoveRx KINOMEscan® screen
A screen of 72 inhibitors against 456 human kinases. Quantitative data were derived using DiscoveRx KINOMEscan® platform.
http://www.discoverx.com/services/drug-discovery-development-services/kinase-profiling/kinomescan
Reference: 1,12

Key to terms and symbols Click column headers to sort
Target used in screen: RIPK1
Ligand Sp. Type Action Affinity Units
tozasertib Hs Inhibitor Inhibition 7.7 pKd
KW-2449 Hs Inhibitor Inhibition 7.2 pKd
AST-487 Hs Inhibitor Inhibition 6.7 pKd
JNJ-28312141 Hs Inhibitor Inhibition 6.6 pKd
pazopanib Hs Inhibitor Inhibition 6.6 pKd
dovitinib Hs Inhibitor Inhibition 6.5 pKd
sunitinib Hs Inhibitor Inhibition 6.4 pKd
foretinib Hs Inhibitor Inhibition 6.1 pKd
quizartinib Hs Inhibitor Inhibition 6.1 pKd
SU-14813 Hs Inhibitor Inhibition 5.9 pKd
Displaying the top 10 most potent ligands  View all ligands in screen »
Immunopharmacology Comments
RIPK1 and RIPK3 are involved in necroptosis [9-11] and RIPK1 and RIPK2 appear to be critical mediators of intestinal homeostasis and drivers of intestinal inflammation [7].
Immuno Process Associations
Immuno Process:  Inflammation
GO Annotations:  Associated to 3 GO processes
GO:0002756 MyD88-independent toll-like receptor signaling pathway TAS
GO:0034138 toll-like receptor 3 signaling pathway TAS
GO:0035666 TRIF-dependent toll-like receptor signaling pathway TAS
Immuno Process:  T cell (activation)
GO Annotations:  Associated to 1 GO processes
GO:0070231 T cell apoptotic process ISS
Immuno Process:  Immune regulation
GO Annotations:  Associated to 4 GO processes
GO:0002756 MyD88-independent toll-like receptor signaling pathway TAS
GO:0034138 toll-like receptor 3 signaling pathway TAS
GO:0035666 TRIF-dependent toll-like receptor signaling pathway TAS
GO:0045651 positive regulation of macrophage differentiation IMP
Immuno Process:  Immune system development
GO Annotations:  Associated to 1 GO processes
GO:0045651 positive regulation of macrophage differentiation IMP
Immuno Process:  Cytokine production & signalling
GO Annotations:  Associated to 6 GO processes
GO:0010803 regulation of tumor necrosis factor-mediated signaling pathway TAS
GO:0032757 positive regulation of interleukin-8 production IDA
GO:0032760 positive regulation of tumor necrosis factor production IDA
GO:0033209 tumor necrosis factor-mediated signaling pathway TAS
GO:0034612 response to tumor necrosis factor IMP
GO:0071356 cellular response to tumor necrosis factor IDA
Immuno Process:  Cellular signalling
GO Annotations:  Associated to 3 GO processes
GO:0002756 MyD88-independent toll-like receptor signaling pathway TAS
GO:0034138 toll-like receptor 3 signaling pathway TAS
GO:0035666 TRIF-dependent toll-like receptor signaling pathway TAS

References

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1. Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP. (2011) Comprehensive analysis of kinase inhibitor selectivity. Nat. Biotechnol.29 (11): 1046-51. [PMID:22037378]

2. Degterev A, Hitomi J, Germscheid M, Ch'en IL, Korkina O, Teng X, Abbott D, Cuny GD, Yuan C, Wagner G et al.. (2008) Identification of RIP1 kinase as a specific cellular target of necrostatins. Nat. Chem. Biol.4 (5): 313-21. [PMID:18408713]

3. Delcommenne M, Tan C, Gray V, Rue L, Woodgett J, Dedhar S. (1998) Phosphoinositide-3-OH kinase-dependent regulation of glycogen synthase kinase 3 and protein kinase B/AKT by the integrin-linked kinase. Proc. Natl. Acad. Sci. U.S.A.95 (19): 11211-6. [PMID:9736715]

4. Delehouzé C, Leverrier-Penna S, Le Cann F, Comte A, Jacquard-Fevai M, Delalande O, Desban N, Baratte B, Gallais I, Faurez F et al.. (2017) 6E11, a highly selective inhibitor of Receptor-Interacting Protein Kinase 1, protects cells against cold hypoxia-reoxygenation injury. Sci Rep7 (1): 12931. [PMID:29018243]

5. Harris PA, Bandyopadhyay D, Berger SB, Campobasso N, Capriotti CA, Cox JA, Dare L, Finger JN, Hoffman SJ, Kahler KM et al.. (2013) Discovery of Small Molecule RIP1 Kinase Inhibitors for the Treatment of Pathologies Associated with Necroptosis. ACS Med Chem Lett4 (12): 1238-43. [PMID:24900635]

6. Harris PA, Berger SB, Jeong JU, Nagilla R, Bandyopadhyay D, Campobasso N, Capriotti CA, Cox JA, Dare L, Dong X et al.. (2017) Discovery of a First-in-Class Receptor Interacting Protein 1 (RIP1) Kinase Specific Clinical Candidate (GSK2982772) for the Treatment of Inflammatory Diseases. J. Med. Chem.60 (4): 1247-1261. [PMID:28151659]

7. Jun JC, Cominelli F, Abbott DW. (2013) RIP2 activity in inflammatory disease and implications for novel therapeutics. J. Leukoc. Biol.94 (5): 927-32. [PMID:23794710]

8. Ren Y, Su Y, Sun L, He S, Meng L, Liao D, Liu X, Ma Y, Liu C, Li S et al.. (2017) Discovery of a Highly Potent, Selective, and Metabolically Stable Inhibitor of Receptor-Interacting Protein 1 (RIP1) for the Treatment of Systemic Inflammatory Response Syndrome. J. Med. Chem.60 (3): 972-986. [PMID:27992216]

9. Rickard JA, O'Donnell JA, Evans JM, Lalaoui N, Poh AR, Rogers T, Vince JE, Lawlor KE, Ninnis RL, Anderton H et al.. (2014) RIPK1 regulates RIPK3-MLKL-driven systemic inflammation and emergency hematopoiesis. Cell157 (5): 1175-88. [PMID:24813849]

10. Silke J, Rickard JA, Gerlic M. (2015) The diverse role of RIP kinases in necroptosis and inflammation. Nat. Immunol.16 (7): 689-97. [PMID:26086143]

11. Vince JE, Silke J. (2016) The intersection of cell death and inflammasome activation. Cell. Mol. Life Sci.73 (11-12): 2349-67. [PMID:27066895]

12. Wodicka LM, Ciceri P, Davis MI, Hunt JP, Floyd M, Salerno S, Hua XH, Ford JM, Armstrong RC, Zarrinkar PP et al.. (2010) Activation state-dependent binding of small molecule kinase inhibitors: structural insights from biochemistry. Chem. Biol.17 (11): 1241-9. [PMID:21095574]

13. Xie T, Peng W, Liu Y, Yan C, Maki J, Degterev A, Yuan J, Shi Y. (2013) Structural Basis of RIP1 Inhibition by Necrostatins. Structure21 (3): 493-9. [PMID:23473668]

How to cite this page

Receptor interacting protein kinase (RIPK) family: receptor interacting serine/threonine kinase 1. Last modified on 09/01/2018. Accessed on 26/04/2018. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2189.