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

Autor: Li W; Department of Molecular & Cell Biology, University of California, Berkeley, Berkeley, CA, USA.; Molecular Biophysics and Bioimaging Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA., Ward FR; Department of Molecular & Cell Biology, University of California, Berkeley, Berkeley, CA, USA., McClure KF; Pfizer Medicinal Chemistry, Pfizer Worldwide Research and Development, Cambridge, MA, USA., Chang ST; Department of Molecular & Cell Biology, University of California, Berkeley, Berkeley, CA, USA., Montabana E; Molecular Biophysics and Bioimaging Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA., Liras S; Pfizer Medicinal Chemistry, Pfizer Worldwide Research and Development, Cambridge, MA, USA., Dullea RG; Cardiovascular, Metabolic and Endocrine Disease Research Unit, Pfizer Worldwide Research and Development, Cambridge, MA, USA., Cate JHD; Department of Molecular & Cell Biology, University of California, Berkeley, Berkeley, CA, USA. jcate@lbl.gov.; Molecular Biophysics and Bioimaging Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA. jcate@lbl.gov.; Department of Chemistry, University of California, Berkeley, Berkeley, CA, USA. jcate@lbl.gov.
Jazyk: angličtina
Zdroj: Nature structural & molecular biology [Nat Struct Mol Biol] 2019 Jun; Vol. 26 (6), pp. 501-509. Date of Electronic Publication: 2019 Jun 03.
DOI: 10.1038/s41594-019-0236-8
Abstrakt: 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.
Databáze: MEDLINE
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