eukaryotic translation initiation factor 2 alpha kinase 4 | GCN2 subfamily | IUPHAR Guide to IMMUNOPHARMACOLOGY

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eukaryotic translation initiation factor 2 alpha kinase 4

  Target has curated data in GtoImmuPdb

Target id: 2018

Nomenclature: eukaryotic translation initiation factor 2 alpha kinase 4

Abbreviated Name: GCN2

Family: GCN2 subfamily

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

Gene and Protein Information
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
GCN2
Database Links
BRENDA
CATH/Gene3D
ChEMBL Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Enzyme
KEGG Gene
OMIM
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Selected 3D Structures
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
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 Parameter Reference
compound A127 [WO2013110309] Hs Inhibition 6.5 pIC50 1
pIC50 6.5 (IC50 3x10-7 M) [1]
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: 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 Affinity Parameter
tamatinib Hs Inhibitor Inhibition 8.5 pKd
lestaurtinib Hs Inhibitor Inhibition 8.4 pKd
staurosporine Hs Inhibitor Inhibition 7.8 pKd
PD-173955 Hs Inhibitor Inhibition 7.6 pKd
midostaurin Hs Inhibitor Inhibition 7.4 pKd
CHIR-265 Hs Inhibitor Inhibition 7.3 pKd
JNJ-28312141 Hs Inhibitor Inhibition 7.1 pKd
neratinib Hs Inhibitor Inhibition 7.0 pKd
fedratinib Hs Inhibitor Inhibition 7.0 pKd
sunitinib 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
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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
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 20/05/2019. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetoimmunopharmacology.org/GRAC/ObjectDisplayForward?objectId=2018.