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-Structure paper
タイトル | Selective inhibition of human translation termination by a drug-like compound. |
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ジャーナル・号・ページ | Nat Commun, Vol. 11, Issue 1, Page 4941, Year 2020 |
掲載日 | 2020年10月2日 |
著者 | Wenfei Li / Stacey Tsai-Lan Chang / Fred R Ward / Jamie H D Cate / |
PubMed 要旨 | Methods to directly inhibit gene expression using small molecules hold promise for the development of new therapeutics targeting proteins that have evaded previous attempts at drug discovery. Among ...Methods to directly inhibit gene expression using small molecules hold promise for the development of new therapeutics targeting proteins that have evaded previous attempts at drug discovery. Among these, small molecules including the drug-like compound PF-06446846 (PF846) selectively inhibit the synthesis of specific proteins, by stalling translation elongation. These molecules also inhibit translation termination by an unknown mechanism. Using cryo-electron microscopy (cryo-EM) and biochemical approaches, we show that PF846 inhibits translation termination by arresting the nascent chain (NC) in the ribosome exit tunnel. The arrested NC adopts a compact α-helical conformation that induces 28 S rRNA nucleotide rearrangements that suppress the peptidyl transferase center (PTC) catalytic activity stimulated by eukaryotic release factor 1 (eRF1). These data support a mechanism of action for a small molecule targeting translation that suppresses peptidyl-tRNA hydrolysis promoted by eRF1, revealing principles of eukaryotic translation termination and laying the foundation for new therapeutic strategies. |
リンク | Nat Commun / PubMed:33009412 / PubMed Central |
手法 | EM (単粒子) |
解像度 | 2.8 - 2.9 Å |
構造データ | EMDB-22085: Selectively stalling of translation termination by a drug-like compound EMDB-22086: |
化合物 | ChemComp-MG: ChemComp-MVM: ChemComp-ZN: ChemComp-K: |
由来 |
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キーワード | RIBOSOME / Selectively stalling / translation termination / drug-like compound / human ribosome |