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eukaryotic translation initiation factor 2 alpha kinase 4

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Immunopharmacology Ligand target has curated data in GtoImmuPdb

Target id: 2018

Nomenclature: eukaryotic translation initiation factor 2 alpha kinase 4

Abbreviated Name: GCN2

Family: GCN2 subfamily

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 1649 15q13.3 EIF2AK4 eukaryotic translation initiation factor 2 alpha kinase 4
Mouse - 1648 2 E5 Eif2ak4 eukaryotic translation initiation factor 2 alpha kinase 4
Rat - 1649 3 q35 Eif2ak4 eukaryotic translation initiation factor 2 alpha kinase 4
Previous and Unofficial Names Click here for help
GCN2
Database Links Click here for help
BRENDA
CATH/Gene3D
ChEMBL Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Enzyme
KEGG Gene
OMIM
Pharos
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  Solution structure of the RWD domain of mouse GCN2
PDB Id:  1UKX
Resolution:  0.0Å
Species:  Mouse
References:  3
Enzyme Reaction Click here for help
EC Number: 2.7.11.1

Download all structure-activity data for this target as a CSV file go icon to follow link

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
compound A127 [WO2013110309] Small molecule or natural product Primary target of this compound Hs Inhibition 6.5 pIC50 1
pIC50 6.5 (IC50 3x10-7 M) [1]
DiscoveRx KINOMEscan® screen Click here for help
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: 2,5

Key to terms and symbols Click column headers to sort
Target used in screen: GCN2(Kin.Dom.2,S808G)
Ligand Sp. Type Action Value Parameter
tamatinib Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 8.5 pKd
lestaurtinib Small molecule or natural product Immunopharmacology Ligand Hs Inhibitor Inhibition 8.4 pKd
staurosporine Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 7.8 pKd
PD-173955 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 7.6 pKd
midostaurin Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 7.4 pKd
CHIR-265 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 7.3 pKd
JNJ-28312141 Small molecule or natural product Hs Inhibitor Inhibition 7.1 pKd
neratinib Small molecule or natural product Approved drug Hs Inhibitor Inhibition 7.0 pKd
fedratinib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition 7.0 pKd
sunitinib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition 6.7 pKd
Displaying the top 10 most potent ligands  View all ligands in screen »
Immunopharmacology Comments
GCN2 is a so-called 'stress kinase'. It phosphorylates serine 51 on the global transcription factor eIF2α upon activation by uncharged tRNA; tRNAs accumulate when amino acid levels are depleted. Phospho-eIF2α blocks translation to cause proliferative arrest.

GCN2 plays several roles in the immune system. It is required for dendritic cell activation and antigen presentation. The GCN2 stress response is required for both optimal proliferation of CD8+ T cells after antigen stimulation, and trafficking to lymphoid organs, i.e. for normal cytotoxic T cell function [4]. GCN2 is dispensable for CD4+ cell proliferation.
Immuno Process Associations
Immuno Process:  Inflammation
GO Annotations:  Associated to 1 GO processes
GO:0002286 T cell activation involved in immune response ISS
Immuno Process:  T cell (activation)
GO Annotations:  Associated to 3 GO processes
GO:0002286 T cell activation involved in immune response ISS
GO:0002821 positive regulation of adaptive immune response ISS
click arrow to show/hide IEA associations
GO:0002250 adaptive immune response IEA
Immuno Process:  B cell (activation)
GO Annotations:  Associated to 2 GO processes
GO:0002821 positive regulation of adaptive immune response ISS
click arrow to show/hide IEA associations
GO:0002250 adaptive immune response IEA
Immuno Process:  Immune regulation
GO Annotations:  Associated to 2 GO processes
GO:0002230 positive regulation of defense response to virus by host ISS
GO:0002821 positive regulation of adaptive immune response ISS
Immuno Process:  Cellular signalling
GO Annotations:  Associated to 1 GO processes
GO:0002286 T cell activation involved in immune response ISS
Clinically-Relevant Mutations and Pathophysiology Click here for help
Disease:  Pulmonary venoocclusive disease 2, autosomal recessive; PVOD2
Synonyms: Pulmonary venoocclusive disease [Orphanet: ORPHA31837] [Disease Ontology: DOID:5453]
Disease Ontology: DOID:5453
OMIM: 234810
Orphanet: ORPHA31837

References

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1. Brazeau JF, Rosse G. (2014) Triazolo[4,5-d]pyrimidine Derivatives as Inhibitors of GCN2. ACS Med Chem Lett, 5 (4): 282-3. [PMID:24900825]

2. 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]

3. Nameki N, Yoneyama M, Koshiba S, Tochio N, Inoue M, Seki E, Matsuda T, Tomo Y, Harada T, Saito K et al.. (2004) Solution structure of the RWD domain of the mouse GCN2 protein. Protein Sci., 13 (8): 2089-100. [PMID:15273307]

4. Van de Velde LA, Guo XJ, Barbaric L, Smith AM, Oguin 3rd TH, Thomas PG, Murray PJ. (2016) Stress Kinase GCN2 Controls the Proliferative Fitness and Trafficking of Cytotoxic T Cells Independent of Environmental Amino Acid Sensing. Cell Rep, 17 (9): 2247-2258. [PMID:27880901]

5. 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]

How to cite this page

GCN2 subfamily: eukaryotic translation initiation factor 2 alpha kinase 4. Last modified on 16/02/2017. Accessed on 31/10/2020. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2018.