| Structural highlights
4g31 is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | , |
| Related: | 3qd2, 4g34 |
| Gene: | EIF2AK3, PEK, PERK (HUMAN) |
| Activity: | Non-specific serine/threonine protein kinase, with EC number 2.7.11.1 |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Disease
[E2AK3_HUMAN] Wolcott-Rallison syndrome. The disease is caused by mutations affecting the gene represented in this entry.[1]
Function
[E2AK3_HUMAN] Phosphorylates the alpha subunit of eukaryotic translation-initiation factor 2 (EIF2), leading to its inactivation and thus to a rapid reduction of translational initiation and repression of global protein synthesis. Serves as a critical effector of unfolded protein response (UPR)-induced G1 growth arrest due to the loss of cyclin-D1 (CCND1) (By similarity).
Publication Abstract from PubMed
PKR-like Endoplasmic Reticulum Kinase (PERK) is activated in response to a variety of endoplasmic reticulum stresses implicated in numerous disease states. Evidence that PERK is implicated in tumorigenesis and cancer cell survival stimulated our search for small molecule inhibitors. Through screening and lead optimization using the human PERK crystal structure, we discovered compound 38 (GSK2606414), an orally available, potent and selective PERK inhibitor. Compound 38 inhibits PERK activation in cells and inhibits the growth of a human tumor xenograft in mice.
Discovery of 7-methyl-5-(1-{[3-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H-indol-5-yl)-7H-p yrrolo[2,3-d]pyrimidin-4-amine (GSK2606414), a Potent and Selective First-in-Class Inhibitor of PKR-like Endoplasmic Reticulum Kinase (PERK).,Axten JM, Medina JR, Feng Y, Shu A, Romeril S, Grant S, Li WH, Heerding DA, Minthorn E, Mencken T, Atkins C, Liu Q, Rabindran S, Kumat R, Hong X, Goetz A, Stanley TB, Taylor D, Sigethy S, Tomberlin GH, Hassell A, Shewchuk LM, Gampe R J Med Chem. 2012 Jul 24. PMID:22827572[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Delepine M, Nicolino M, Barrett T, Golamaully M, Lathrop GM, Julier C. EIF2AK3, encoding translation initiation factor 2-alpha kinase 3, is mutated in patients with Wolcott-Rallison syndrome. Nat Genet. 2000 Aug;25(4):406-9. PMID:10932183 doi:http://dx.doi.org/10.1038/78085
- ↑ Axten JM, Medina JR, Feng Y, Shu A, Romeril S, Grant S, Li WH, Heerding DA, Minthorn E, Mencken T, Atkins C, Liu Q, Rabindran S, Kumat R, Hong X, Goetz A, Stanley TB, Taylor D, Sigethy S, Tomberlin GH, Hassell A, Shewchuk LM, Gampe R. Discovery of 7-methyl-5-(1-{[3-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H-indol-5-yl)-7H-p yrrolo[2,3-d]pyrimidin-4-amine (GSK2606414), a Potent and Selective First-in-Class Inhibitor of PKR-like Endoplasmic Reticulum Kinase (PERK). J Med Chem. 2012 Jul 24. PMID:22827572 doi:10.1021/jm300713s
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