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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

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 1649 15q15.1 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 (general control nonderepressible 2) kinase
Database Links Click here for help
Alphafold Q9P2K8 (Hs), Q9QZ05 (Mm)
BRENDA 2.7.11.1
CATH/Gene3D 3.10.110.10, 3.40.50.800
ChEMBL Target CHEMBL5358 (Hs)
Ensembl Gene ENSG00000128829 (Hs), ENSMUSG00000005102 (Mm), ENSRNOG00000006027 (Rn)
Entrez Gene 440275 (Hs), 27103 (Mm), 114859 (Rn)
Human Protein Atlas ENSG00000128829 (Hs)
KEGG Enzyme 2.7.11.1
KEGG Gene hsa:440275 (Hs), mmu:27103 (Mm), rno:114859 (Rn)
OMIM 609280 (Hs)
Pharos Q9P2K8 (Hs)
RefSeq Nucleotide NM_001013703 (Hs), NM_013719 (Mm), NM_001105744 (Rn)
RefSeq Protein NP_001013725 (Hs), NP_038747 (Mm), NP_001099214 (Rn)
UniProtKB Q9P2K8 (Hs), Q9QZ05 (Mm)
Wikipedia EIF2AK4 (Hs)
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:  4
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

Activators
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
HC-7366 Small molecule or natural product Hs Activation 7.9 pIC50 5
⤷ pIC50 7.9 (IC50 1.2x10-8 M) [5]
Description: Determined in a GCN2 biochemical assay
Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
compound 39 [PMID: 36127295] Small molecule or natural product Hs Inhibition 8.3 pIC50 3
⤷ pIC50 8.3 (IC50 5x10-9 M) [3]
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: 2,7
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 Ligand has a PDB structure 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 [6]. GCN2 is dispensable for CD4+ cell proliferation.
Immuno Process Associations
Immuno Process:  Inflammation
Immuno Process:  T cell (activation)
Immuno Process:  B cell (activation)
Immuno Process:  Immune regulation
Immuno Process:  Cellular signalling
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. Jackson JJ, Shibuya GM, Ravishankar B, Adusumilli L, Bradford D, Brockstedt DG, Bucher C, Bui M, Cho C, Colas C et al.. (2022) Potent GCN2 Inhibitor Capable of Reversing MDSC-Driven T Cell Suppression Demonstrates In Vivo Efficacy as a Single Agent and in Combination with Anti-Angiogenesis Therapy. J Med Chem, 65 (19): 12895-12924. [PMID:36127295]

4. 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]

5. Thomson CG, Aicher TD, Cheng W, Du H, Dudgeon C, Li AH, Li B, Lightcap E, Luo D, Mulvihill M et al.. (2024) Discovery of HC-7366: An Orally Bioavailable and Efficacious GCN2 Kinase Activator. J Med Chem, 67 (7): 5259-5271. [PMID:38530741]

6. 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]

7. 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 22/04/2024. Accessed on 13/01/2025. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2018.