6OM0

Human ribosome nascent chain complex (PCSK9-RNC) stalled by a drug-like molecule with AP and PE tRNAs

This is a non-PDB format compatible entry.

Summary for 6OM0

• Entry DOI: 10.2210/pdb6om0/pdb
• EMDB information: 0526 0596 0597 0598 0599 0600 0601
• Descriptor: 18S ribosomal RNA, 40S ribosomal protein S11, 40S ribosomal protein S15, ... (87 entities in total)
• Functional Keywords: selective stalling, drug-like molecule, human ribosome nascent chain complex, ribosome
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 83
• Total formula weight: 3175175.79

Authors

Li, W.,Cate, J.H.D. (deposition date: 2019-04-17, release date: 2019-06-19, Last modification date: 2024-11-13)

Primary citation

Li, W.,Ward, F.R.,McClure, K.F.,Chang, S.T.,Montabana, E.,Liras, S.,Dullea, R.G.,Cate, J.H.D.
Structural basis for selective stalling of human ribosome nascent chain complexes by a drug-like molecule.
Nat.Struct.Mol.Biol., 26:501-509, 2019

PubMed 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.

PubMed: 31160784
DOI: 10.1038/s41594-019-0236-8

Experimental method

ELECTRON MICROSCOPY (3.1 Å)