7qq6 | pdb_00007qq6
GCN2 (EIF2ALPHA KINASE 4, E2AK4) IN COMPLEX WITH COMPOUND 1 (dovitinib)
Structural highlights
DiseaseE2AK4_HUMAN Pulmonary venoocclusive disease;Pulmonary capillary hemangiomatosis;Heritable pulmonary arterial hypertension. The disease is caused by mutations affecting the gene represented in this entry. FunctionE2AK4_HUMAN Metabolic-stress sensing protein kinase that phosphorylates the alpha subunit of eukaryotic translation initiation factor 2 (eIF-2-alpha/EIF2S1) on 'Ser-52' in response to low amino acid availability (PubMed:25329545). Plays a role as an activator of the integrated stress response (ISR) required for adapatation to amino acid starvation. Converts phosphorylated eIF-2-alpha/EIF2S1 either to a competitive inhibitor of the translation initiation factor eIF-2B, leading to a global protein synthesis repression, and thus to a reduced overall utilization of amino acids, or to a translational initiation activation of specific mRNAs, such as the transcriptional activator ATF4, and hence allowing ATF4-mediated reprogramming of amino acid biosynthetic gene expression to alleviate nutrient depletion. Binds uncharged tRNAs (By similarity). Involved in cell cycle arrest by promoting cyclin D1 mRNA translation repression after the unfolded protein response pathway (UPR) activation or cell cycle inhibitor CDKN1A/p21 mRNA translation activation in response to amino acid deprivation (PubMed:26102367). Plays a role in the consolidation of synaptic plasticity, learning as well as formation of long-term memory. Plays a role in neurite outgrowth inhibition. Plays a proapoptotic role in response to glucose deprivation. Promotes global cellular protein synthesis repression in response to UV irradiation independently of the stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) and p38 MAPK signaling pathways (By similarity). Plays a role in the antiviral response against alphavirus infection; impairs early viral mRNA translation of the incoming genomic virus RNA, thus preventing alphavirus replication (By similarity).[UniProtKB:P15442][UniProtKB:Q9QZ05][1] [2] (Microbial infection) Plays a role in modulating the adaptive immune response to yellow fever virus infection; promotes dendritic cells to initiate autophagy and antigene presentation to both CD4(+) and CD8(+) T-cells under amino acid starvation (PubMed:24310610).[3] Publication Abstract from PubMedWhen activated by amino acid starvation, the stress sensing protein kinase GCN2 phosphorylates the eukaryotic initiation factor 2 alpha, inhibiting translation to conserve energy and facilitate cell survival. Amino acid starvation, particularly of tryptophan and arginine, affects immune tolerance by suppressing differentiation and proliferation of T-cells via activation of GCN2 kinase. In addition, the GCN2 pathway mediates cancer survival directly within the context of metabolic stress. Here, we report the first crystal structures of the human GCN2 kinase domain (KD) in complex with two inhibitors of different size, shape, and chemical scaffold. Three novel activation loop conformations representative of different activation states of the kinase are described. In addition, a novel dimerization organization for GCN2 is observed. This arrangement is consistent with the hypothesis that the GCN2 KD forms an antiparallel inactive dimer until uncharged tRNA binds to it and triggers conformational changes that shift the equilibrium to the active parallel dimer. The structure of human GCN2 reveals a parallel, back-to-back kinase dimer with a plastic DFG activation loop motif.,Maia de Oliveira T, Korboukh V, Caswell S, Winter Holt JJ, Lamb M, Hird AW, Overman R Biochem J. 2020 Jan 17;477(1):275-284. doi: 10.1042/BCJ20190196. PMID:31868900[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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