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-Structure paper
タイトル | Structural basis for selective stalling of human ribosome nascent chain complexes by a drug-like molecule. |
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ジャーナル・号・ページ | Nat Struct Mol Biol, Vol. 26, Issue 6, Page 501-509, Year 2019 |
掲載日 | 2019年6月3日 |
著者 | Wenfei Li / Fred R Ward / Kim F McClure / Stacey Tsai-Lan Chang / Elizabeth Montabana / Spiros Liras / Robert G Dullea / Jamie H D Cate / |
PubMed 要旨 | The drug-like molecule PF-06446846 (PF846) binds the human ribosome and selectively blocks the translation of a small number of proteins by an unknown mechanism. In structures of PF846-stalled human ...The drug-like molecule PF-06446846 (PF846) binds the human ribosome and selectively blocks the translation of a small number of proteins by an unknown mechanism. In structures of PF846-stalled human ribosome nascent chain complexes, PF846 binds in the ribosome exit tunnel in a eukaryotic-specific pocket formed by 28S ribosomal RNA, and alters the path of the nascent polypeptide chain. PF846 arrests the translating ribosome in the rotated state of translocation, in which the peptidyl-transfer RNA 3'-CCA end is improperly docked in the peptidyl transferase center. Selections of messenger RNAs from mRNA libraries using translation extracts reveal that PF846 can stall translation elongation, arrest termination or even enhance translation, depending on nascent chain sequence context. These results illuminate how a small molecule selectively targets translation by the human ribosome, and provides a foundation for developing small molecules that modulate the production of proteins of therapeutic interest. |
リンク | Nat Struct Mol Biol / PubMed:31160784 / PubMed Central |
手法 | EM (単粒子) |
解像度 | 3.0 - 4.7 Å |
構造データ | EMDB-0526: Structure of drug-like molecule stalled USO1 ribosome nascent chain complex (human) EMDB-0596: Structure of a drug-like molecule stalled PCSK9 ribosome nascent chain complex (PCSK9-RNC) with AP tRNA and PE tRNA EMDB-0597: Structure of a drug-like molecule stalled ribosome nascent chain complex (PCSK9-RNC) in rotated state with AA tRAN and PE tRNA EMDB-0598: Structure of a drug-like molecule stalled ribosome nascent chain complex (PCSK9_RNC) in non-rotated state with PP tRNA EMDB-0599: Structure of a drug-like molecule stalled CDH1 ribosome nascent chain complex (CDH1-RNC) in rotated state with AA tRNA and PE tRNA EMDB-0600: Human ribosome nascent chain complex (CDH1-RNC) stalled by a drug-like molecule with AP tRNA and PE tRNA EMDB-0601: Human ribosome nascent chain complex (CDH1-RNC) stalled by a drug-like molecule with PP tRNA EMDB-20134: EMDB-20135: |
化合物 | ChemComp-MG: ChemComp-ZN: ChemComp-MVM: ChemComp-HOH: |
由来 |
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キーワード | RIBOSOME / selective stalling / drug-like molecule / human ribosome nascent chain complex / drug-like small molecule |