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Structural basis for selective stalling of human ribosome nascent chain complexes by a drug-like molecule.

Li W, Ward FR, McClure KF, Chang ST, Montabana E, Liras S, Dullea RG, Cate JHD
Nat Struct Mol Biol 26 501-509 (2019)
Related entries: 6ole, 6olf, 6olg, 6oli, 6olz, 6om7

Cited: 36 times
EuropePMC logo PMID: 31160784

Abstract

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.

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  23. The eRF1 degrader SRI-41315 acts as a molecular glue at the ribosomal decoding center. Coelho JPL, Yip MCJ, Oltion K, Taunton J, Shao S. Nat Chem Biol (2024)


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