Ensemble cryo-EM elucidates the mechanism of translation fidelity

Nature. 2017 Jun 1;546(7656):113-117. doi: 10.1038/nature22397. Epub 2017 May 24.

Abstract

Gene translation depends on accurate decoding of mRNA, the structural mechanism of which remains poorly understood. Ribosomes decode mRNA codons by selecting cognate aminoacyl-tRNAs delivered by elongation factor Tu (EF-Tu). Here we present high-resolution structural ensembles of ribosomes with cognate or near-cognate aminoacyl-tRNAs delivered by EF-Tu. Both cognate and near-cognate tRNA anticodons explore the aminoacyl-tRNA-binding site (A site) of an open 30S subunit, while inactive EF-Tu is separated from the 50S subunit. A transient conformation of decoding-centre nucleotide G530 stabilizes the cognate codon-anticodon helix, initiating step-wise 'latching' of the decoding centre. The resulting closure of the 30S subunit docks EF-Tu at the sarcin-ricin loop of the 50S subunit, activating EF-Tu for GTP hydrolysis and enabling accommodation of the aminoacyl-tRNA. By contrast, near-cognate complexes fail to induce the G530 latch, thus favouring open 30S pre-accommodation intermediates with inactive EF-Tu. This work reveals long-sought structural differences between the pre-accommodation of cognate and near-cognate tRNAs that elucidate the mechanism of accurate decoding.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anticodon / chemistry
  • Anticodon / genetics
  • Anticodon / ultrastructure
  • Codon / chemistry
  • Codon / genetics
  • Codon / ultrastructure
  • Cryoelectron Microscopy*
  • Escherichia coli / chemistry
  • Escherichia coli / genetics
  • Escherichia coli / ultrastructure
  • GTP Phosphohydrolases / metabolism
  • GTP Phosphohydrolases / ultrastructure
  • Guanosine Triphosphate / metabolism
  • Hydrolysis
  • Models, Molecular
  • Peptide Elongation Factor Tu / metabolism
  • Peptide Elongation Factor Tu / ultrastructure
  • Protein Biosynthesis*
  • Protein Domains
  • RNA, Ribosomal, 16S / genetics
  • RNA, Ribosomal, 16S / metabolism
  • RNA, Ribosomal, 16S / ultrastructure
  • RNA, Transfer, Amino Acyl / genetics
  • RNA, Transfer, Amino Acyl / metabolism
  • RNA, Transfer, Amino Acyl / ultrastructure
  • Ribosome Subunits / chemistry
  • Ribosome Subunits / metabolism
  • Ribosome Subunits / ultrastructure
  • Ribosomes / chemistry
  • Ribosomes / metabolism*
  • Ribosomes / ultrastructure*

Substances

  • Anticodon
  • Codon
  • RNA, Ribosomal, 16S
  • RNA, Transfer, Amino Acyl
  • Guanosine Triphosphate
  • GTP Phosphohydrolases
  • Peptide Elongation Factor Tu