6u09

Discovery of Lysine-Targeted eIF4E Inhibitors through Covalent Docking

spinqualitylabelsall models 6u09, resolution 1.79Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6u09 is a 4 chain structure with sequence from Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.79Å Ligands: EI9 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function IF4E_MOUSE Recognizes and binds the 7-methylguanosine-containing mRNA cap during an early step in the initiation of protein synthesis and facilitates ribosome binding by inducing the unwinding of the mRNAs secondary structures. May play an important role in spermatogenesis through translational regulation of stage-specific mRNAs during germ cell development (By similarity). Its translation stimulation activity is repressed by binding to the complex CYFIP1-FMR1. Component of the CYFIP1-EIF4E-FMR1 complex which binds to the mRNA cap and mediates translational repression. In the CYFIP1-EIF4E-FMR1 complex this subunit mediates the binding to the mRNA cap. Publication Abstract from PubMed Eukaryotic translation initiation factor 4E (eIF4E) binds the m7GTP cap structure at the 5'-end of mRNAs, stimulating the translation of proteins implicated in cancer cell growth and metastasis. eIF4E is a notoriously challenging target, and most of the reported inhibitors are negatively charged guanine analogues with negligible cell permeability. To overcome these challenges, we envisioned a covalent targeting strategy. As there are no cysteines near the eIF4E cap binding site, we developed a covalent docking approach focused on lysine. Taking advantage of a "make-on-demand" virtual library, we used covalent docking to identify arylsulfonyl fluorides that target a noncatalytic lysine (Lys162) in eIF4E. Guided by cocrystal structures, we elaborated arylsulfonyl fluoride 2 to 12, which to our knowledge is the first covalent eIF4E inhibitor with cellular activity. In addition to providing a new tool for acutely inactivating eIF4E in cells, our computational approach may offer a general strategy for developing selective lysine-targeted covalent ligands. Discovery of Lysine-Targeted eIF4E Inhibitors through Covalent Docking.,Wan X, Yang T, Cuesta A, Pang X, Balius TE, Irwin JJ, Shoichet BK, Taunton J J Am Chem Soc. 2020 Mar 4. doi: 10.1021/jacs.9b10377. PMID:32105459 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Eukaryotic initiation factor 3D structures

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