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TitleStructural basis for selective stalling of human ribosome nascent chain complexes by a drug-like molecule.
Journal, issue, pagesNat Struct Mol Biol, Vol. 26, Issue 6, Page 501-509, Year 2019
Publish dateJun 3, 2019
AuthorsWenfei Li / Fred R Ward / Kim F McClure / Stacey Tsai-Lan Chang / Elizabeth Montabana / Spiros Liras / Robert G Dullea / Jamie H D Cate /
PubMed AbstractThe 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.
External linksNat Struct Mol Biol / PubMed:31160784 / PubMed Central
MethodsEM (single particle)
Resolution3.0 - 4.7 Å
Structure data

EMDB-0526: Structure of drug-like molecule stalled USO1 ribosome nascent chain complex (human)
PDB-6oli: Structure of human ribosome nascent chain complex selectively stalled by a drug-like small molecule (USO1-RNC)
Method: EM (single particle) / Resolution: 3.5 Å

EMDB-0596: Structure of a drug-like molecule stalled PCSK9 ribosome nascent chain complex (PCSK9-RNC) with AP tRNA and PE tRNA
PDB-6om0: Human ribosome nascent chain complex (PCSK9-RNC) stalled by a drug-like molecule with AP and PE tRNAs
Method: EM (single particle) / Resolution: 3.08 Å

EMDB-0597: Structure of a drug-like molecule stalled ribosome nascent chain complex (PCSK9-RNC) in rotated state with AA tRAN and PE tRNA
PDB-6om7: Human ribosome nascent chain complex (PCSK9-RNC) stalled by a drug-like small molecule with AA and PE tRNAs
Method: EM (single particle) / Resolution: 3.72 Å

EMDB-0598: Structure of a drug-like molecule stalled ribosome nascent chain complex (PCSK9_RNC) in non-rotated state with PP tRNA
PDB-6olz: Human ribosome nascent chain complex (PCSK9-RNC) stalled by a drug-like molecule with PP tRNA
Method: EM (single particle) / Resolution: 3.9 Å

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
PDB-6olf: Human ribosome nascent chain complex (CDH1-RNC) stalled by a drug-like molecule with AA and PE tRNAs
Method: EM (single particle) / Resolution: 3.9 Å

EMDB-0600: Human ribosome nascent chain complex (CDH1-RNC) stalled by a drug-like molecule with AP tRNA and PE tRNA
PDB-6ole: Human ribosome nascent chain complex (CDH1-RNC) stalled by a drug-like molecule with AP and PE tRNAs
Method: EM (single particle) / Resolution: 3.0 Å

EMDB-0601: Human ribosome nascent chain complex (CDH1-RNC) stalled by a drug-like molecule with PP tRNA
PDB-6olg: Human ribosome nascent chain complex stalled by a drug-like small molecule (CDH1_RNC with PP tRNA)
Method: EM (single particle) / Resolution: 3.4 Å

EMDB-20134:
Structure of a drug-like molecule stalled PCSK9 ribosome nascent chain complex (PCSK9-RNC) with AP tRNA and PE tRNA (sample prepared with a short incubation time)
Method: EM (single particle) / Resolution: 4.7 Å

EMDB-20135:
Structure of a drug-like molecule stalled PCSK9 ribosome nascent chain complex (PCSK9-RNC) with PP tRNA (sample prepared with a short incubation time)
Method: EM (single particle) / Resolution: 4.6 Å

Chemicals

ChemComp-MG:
Unknown entry

ChemComp-ZN:
Unknown entry

ChemComp-MVM:
N-(3-chloropyridin-2-yl)-N-[(3R)-piperidin-3-yl]-4-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)benzamide

ChemComp-HOH:
WATER

Source
  • homo sapiens (human)
KeywordsRIBOSOME / selective stalling / drug-like molecule / human ribosome nascent chain complex / drug-like small molecule

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