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Structure paper

TitlemRNA decoding in human is kinetically and structurally distinct from bacteria.
Journal, issue, pagesNature, Vol. 617, Issue 7959, Page 200-207, Year 2023
Publish dateApr 5, 2023
AuthorsMikael Holm / S Kundhavai Natchiar / Emily J Rundlet / Alexander G Myasnikov / Zoe L Watson / Roger B Altman / Hao-Yuan Wang / Jack Taunton / Scott C Blanchard /
PubMed AbstractIn all species, ribosomes synthesize proteins by faithfully decoding messenger RNA (mRNA) nucleotide sequences using aminoacyl-tRNA substrates. Current knowledge of the decoding mechanism derives ...In all species, ribosomes synthesize proteins by faithfully decoding messenger RNA (mRNA) nucleotide sequences using aminoacyl-tRNA substrates. Current knowledge of the decoding mechanism derives principally from studies on bacterial systems. Although key features are conserved across evolution, eukaryotes achieve higher-fidelity mRNA decoding than bacteria. In human, changes in decoding fidelity are linked to ageing and disease and represent a potential point of therapeutic intervention in both viral and cancer treatment. Here we combine single-molecule imaging and cryogenic electron microscopy methods to examine the molecular basis of human ribosome fidelity to reveal that the decoding mechanism is both kinetically and structurally distinct from that of bacteria. Although decoding is globally analogous in both species, the reaction coordinate of aminoacyl-tRNA movement is altered on the human ribosome and the process is an order of magnitude slower. These distinctions arise from eukaryote-specific structural elements in the human ribosome and in the elongation factor eukaryotic elongation factor 1A (eEF1A) that together coordinate faithful tRNA incorporation at each mRNA codon. The distinct nature and timing of conformational changes within the ribosome and eEF1A rationalize how increased decoding fidelity is achieved and potentially regulated in eukaryotic species.
External linksNature / PubMed:37020024 / PubMed Central
MethodsEM (single particle)
Resolution1.67 - 2.94 Å
Structure data

EMDB-29757, PDB-8g5y:
mRNA decoding in human is kinetically and structurally distinct from bacteria (IC state)
Method: EM (single particle) / Resolution: 2.29 Å

EMDB-29758, PDB-8g5z:
mRNA decoding in human is kinetically and structurally distinct from bacteria (GA state)
Method: EM (single particle) / Resolution: 2.64 Å

EMDB-29759, PDB-8g60:
mRNA decoding in human is kinetically and structurally distinct from bacteria (CR state)
Method: EM (single particle) / Resolution: 2.54 Å

EMDB-29760, PDB-8g61:
mRNA decoding in human is kinetically and structurally distinct from bacteria (AC state)
Method: EM (single particle) / Resolution: 2.94 Å

EMDB-29766: mRNA decoding in human is kinetically and structurally distinct from bacteria (60S Focus refined map)
Method: EM (single particle) / Resolution: 1.7 Å

EMDB-29768: mRNA decoding in human is kinetically and structurally distinct from bacteria (40S Focus refined map)
Method: EM (single particle) / Resolution: 1.8 Å

EMDB-29771, PDB-8g6j:
mRNA decoding in human is kinetically and structurally distinct from bacteria (GA state 2)
Method: EM (single particle) / Resolution: 2.8 Å

EMDB-29782: mRNA decoding in human is kinetically and structurally distinct from bacteria (80S consensus refined structure)
Method: EM (single particle) / Resolution: 2.1 Å

EMDB-40205, PDB-8glp:
mRNA decoding in human is kinetically and structurally distinct from bacteria (Consensus LSU focused refined structure)
Method: EM (single particle) / Resolution: 1.67 Å

Chemicals

ChemComp-SPD:
SPERMIDINE / Spermidine

ChemComp-PUT:
1,4-DIAMINOBUTANE / Putrescine

ChemComp-K:
Unknown entry

ChemComp-MG:
Unknown entry

ChemComp-ANM:
ANISOMYCIN / antibiotic*YM / Anisomycin

ChemComp-3H3:
4-{(2R,5S,6E)-2-hydroxy-5-methyl-7-[(2R,3S,4E,6Z,10E)-3-methyl-12-oxooxacyclododeca-4,6,10-trien-2-yl]-4-oxooct-6-en-1-yl}piperidine-2,6-dione

ChemComp-ZN:
Unknown entry

ChemComp-MET:
METHIONINE / Methionine

ChemComp-HOH:
WATER / Water

ChemComp-PHE:
PHENYLALANINE / Phenylalanine

ChemComp-GSP:
5'-GUANOSINE-DIPHOSPHATE-MONOTHIOPHOSPHATE

ChemComp-ZIY:
plitidepsin

ChemComp-3HE:
4-{(2R)-2-[(1S,3S,5S)-3,5-dimethyl-2-oxocyclohexyl]-2-hydroxyethyl}piperidine-2,6-dione / Cycloheximide

ChemComp-HMT:
(3beta)-O~3~-[(2R)-2,6-dihydroxy-2-(2-methoxy-2-oxoethyl)-6-methylheptanoyl]cephalotaxine / anticancer, alkaloid*YM / Omacetaxine mepesuccinate

ChemComp-YRB:
(3R,6R,9S,12S,15S,18S,20R,24aR)-6-[(2S)-butan-2-yl]-3,12-bis[(1R)-1-hydroxy-2-methylpropyl]-8,9,11,17,18-pentamethyl-15-[(2S)-2-methylbutyl]hexadecahydropyrido[1,2-a][1,4,7,10,13,16,19]heptaazacyclohenicosine-1,4,7,10,13,16,19(21H)-heptone

ChemComp-TRS:
2-AMINO-2-HYDROXYMETHYL-PROPANE-1,3-DIOL / pH buffer*YM / Tris

Source
  • homo sapiens (human)
  • escherichia coli (E. coli)
KeywordsRIBOSOME / Human 80S / tRNA / mRNA eEF1A / eIF5A / tRNA selection / mRNA tRNA selection

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