6U09
Discovery of Lysine-Targeted eIF4E Inhibitors through Covalent Docking
Summary for 6U09
| Entry DOI | 10.2210/pdb6u09/pdb |
| Related | 6U06 |
| Descriptor | Eukaryotic translation initiation factor 4E, 3-{(1-oxo-1,2-dihydroisoquinolin-7-yl)[(pyridin-4-yl)methyl]sulfamoyl}benzene-1-sulfonyl fluoride (3 entities in total) |
| Functional Keywords | cap-binding site, anti-neoplastic, inhibitor, translation initiation blocking, translation-inhibitor complex, translation/inhibitor |
| Biological source | Mus musculus (Mouse) |
| Total number of polymer chains | 4 |
| Total formula weight | 90474.44 |
| Authors | Wan, X.B.,Shoichet, B.K.,Taunton, J. (deposition date: 2019-08-13, release date: 2019-10-23, Last modification date: 2024-10-16) |
| Primary citation | Wan, X.,Yang, T.,Cuesta, A.,Pang, X.,Balius, T.E.,Irwin, J.J.,Shoichet, B.K.,Taunton, J. Discovery of Lysine-Targeted eIF4E Inhibitors through Covalent Docking. J.Am.Chem.Soc., 142:4960-4964, 2020 Cited by PubMed Abstract: 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 to , 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. PubMed: 32105459DOI: 10.1021/jacs.9b10377 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.79 Å) |
Structure validation
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