6XA1

Structure of a drug-like compound stalled human translation termination complex

This is a non-PDB format compatible entry.

Summary for 6XA1

• Entry DOI: 10.2210/pdb6xa1/pdb
• EMDB information: 22085
• Descriptor: 60S ribosomal protein L8, 60S ribosomal protein L7a, 60S ribosomal protein L9, ... (87 entities in total)
• Functional Keywords: selectively stalling, translation termination, drug-like compound, human ribosome, ribosome
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 83
• Total formula weight: 3134503.88

Authors

Li, W.,Cate, J. (deposition date: 2020-06-03, release date: 2020-10-07, Last modification date: 2024-12-25)

Primary citation

Li, W.,Chang, S.T.,Ward, F.R.,Cate, J.H.D.
Selective inhibition of human translation termination by a drug-like compound.
Nat Commun, 11:4941-4941, 2020

PubMed Abstract: Methods to directly inhibit gene expression using small molecules hold promise for the development of new therapeutics targeting proteins that have evaded previous attempts at drug discovery. Among these, small molecules including the drug-like compound PF-06446846 (PF846) selectively inhibit the synthesis of specific proteins, by stalling translation elongation. These molecules also inhibit translation termination by an unknown mechanism. Using cryo-electron microscopy (cryo-EM) and biochemical approaches, we show that PF846 inhibits translation termination by arresting the nascent chain (NC) in the ribosome exit tunnel. The arrested NC adopts a compact α-helical conformation that induces 28 S rRNA nucleotide rearrangements that suppress the peptidyl transferase center (PTC) catalytic activity stimulated by eukaryotic release factor 1 (eRF1). These data support a mechanism of action for a small molecule targeting translation that suppresses peptidyl-tRNA hydrolysis promoted by eRF1, revealing principles of eukaryotic translation termination and laying the foundation for new therapeutic strategies.

PubMed: 33009412
DOI: 10.1038/s41467-020-18765-2

Experimental method

ELECTRON MICROSCOPY (2.8 Å)