5wvd
Structure of Mnk1 in complex with DS12881479
Structural highlights
FunctionMKNK1_HUMAN May play a role in the response to environmental stress and cytokines. Appears to regulate translation by phosphorylating EIF4E, thus increasing the affinity of this protein for the 7-methylguanosine-containing mRNA cap.[1] [2] [3] [4] Publication Abstract from PubMedMitogen-activated protein kinase (MAPK)-interacting kinases 1 (Mnk1) and 2 (Mnk2) modulate translation initiation through the phosphorylation of eukaryotic translation initiation factor 4E, which promotes tumorigenesis. However, Mnk1 and Mnk2 are dispensable in normal cells, suggesting that the inhibition of Mnk1 and Mnk2 could be effective in cancer therapy. To provide a structural basis for Mnk1 inhibition, a novel Mnk1 inhibitor was discovered and the crystal structure of Mnk1 in complex with this inhibitor was determined. The crystal structure revealed that the inhibitor binds to the autoinhibited state of Mnk1, stabilizing the Mnk-specific DFD motif in the DFD-out conformation, thus preventing Mnk1 from switching to the active conformation and thereby inhibiting the kinase activity. These results provide a valuable platform for the structure-guided design of Mnk1 inhibitors. A novel inhibitor stabilizes the inactive conformation of MAPK-interacting kinase 1.,Matsui Y, Yasumatsu I, Yoshida KI, Iimura S, Ikeno Y, Nawano T, Fukano H, Ubukata O, Hanzawa H, Tanzawa F, Isoyama T Acta Crystallogr F Struct Biol Commun. 2018 Mar 1;74(Pt 3):156-160. doi:, 10.1107/S2053230X18002108. Epub 2018 Feb 26. PMID:29497019[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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