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TitleThe chemical landscape of the human ribosome at 1.67 Å resolution.
Journal, issue, pagesbioRxiv, Year 2023
Publish dateFeb 28, 2023
AuthorsAlexandre Faille / Kyle C Dent / Simone Pellegrino / Pekka Jaako / Alan J Warren
PubMed AbstractThe ability of ribosomes to translate the genetic code into protein requires a finely tuned ion and solvent ecosystem. However, the lack of high-resolution structures has precluded accurate ...The ability of ribosomes to translate the genetic code into protein requires a finely tuned ion and solvent ecosystem. However, the lack of high-resolution structures has precluded accurate positioning of all the functional elements of the ribosome and limited our understanding of the specific role of ribosomal RNA chemical modifications in modulating ribosome function in health and disease. Here, using a new sample preparation methodology based on functionalised pristine graphene-coated grids, we solve the cryo-EM structure of the human large ribosomal subunit to a resolution of 1.67 Å. The accurate assignment of water molecules, magnesium and potassium ions in our model highlights the fundamental biological role of ribosomal RNA methylation in harnessing unconventional carbon-oxygen hydrogen bonds to establish chemical interactions with the environment and fine-tune the functional interplay with tRNA. In addition, the structures of three translational inhibitors bound to the human large ribosomal subunit at better than 2 Å resolution provide mechanistic insights into how three key druggable pockets of the ribosome are targeted and illustrate the potential of this methodology to accelerate high-throughput structure-based design of anti-cancer therapeutics.
External linksbioRxiv / PubMed:36909531 / PubMed Central
MethodsEM (single particle)
Resolution1.67 Å
Structure data

15113

8a3d

EMDB-15113, PDB-8a3d:
Human mature large subunit of the ribosome with eIF6 and homoharringtonine bound
Method: EM (single particle) / Resolution: 1.67 Å

Chemicals

ChemComp-MG:
Unknown entry

ChemComp-K:
Unknown entry

ChemComp-NA:
Unknown entry

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

ChemComp-SPM:
SPERMINE / Spermine

ChemComp-EPE:
4-(2-HYDROXYETHYL)-1-PIPERAZINE ETHANESULFONIC ACID / pH buffer*YM / HEPES

ChemComp-ZN:
Unknown entry

ChemComp-HOH:
WATER / Water

Source
  • homo sapiens (human)
  • human (human)
KeywordsTRANSLATION / Ribosome / human / rna modifications / water / magnesium / potassium / homoharringtonine

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