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Structure paper

TitleMolecular basis of the pleiotropic effects by the antibiotic amikacin on the ribosome.
Journal, issue, pagesNat Commun, Vol. 14, Issue 1, Page 4666, Year 2023
Publish dateAug 3, 2023
AuthorsSavannah M Seely / Narayan P Parajuli / Arindam De Tarafder / Xueliang Ge / Suparna Sanyal / Matthieu G Gagnon /
PubMed AbstractAminoglycosides are a class of antibiotics that bind to ribosomal RNA and exert pleiotropic effects on ribosome function. Amikacin, the semisynthetic derivative of kanamycin, is commonly used for ...Aminoglycosides are a class of antibiotics that bind to ribosomal RNA and exert pleiotropic effects on ribosome function. Amikacin, the semisynthetic derivative of kanamycin, is commonly used for treating severe infections with multidrug-resistant, aerobic Gram-negative bacteria. Amikacin carries the 4-amino-2-hydroxy butyrate (AHB) moiety at the N amino group of the central 2-deoxystreptamine (2-DOS) ring, which may confer amikacin a unique ribosome inhibition profile. Here we use in vitro fast kinetics combined with X-ray crystallography and cryo-EM to dissect the mechanisms of ribosome inhibition by amikacin and the parent compound, kanamycin. Amikacin interferes with tRNA translocation, release factor-mediated peptidyl-tRNA hydrolysis, and ribosome recycling, traits attributed to the additional interactions amikacin makes with the decoding center. The binding site in the large ribosomal subunit proximal to the 3'-end of tRNA in the peptidyl (P) site lays the groundwork for rational design of amikacin derivatives with improved antibacterial properties.
External linksNat Commun / PubMed:37537169 / PubMed Central
MethodsEM (single particle) / X-ray diffraction
Resolution2.89 - 2.946 Å
Structure data

40882

8syl

EMDB-40882, PDB-8syl:
Cryo-EM structure of the Escherichia coli 70S ribosome in complex with amikacin, mRNA, and A-, P-, and E-site tRNAs
Method: EM (single particle) / Resolution: 2.9 Å

PDB-8ev6:
Crystal structure of the Thermus thermophilus 70S ribosome in complex with amikacin, mRNA, and A-, P-, and E-site tRNAs
Method: X-RAY DIFFRACTION / Resolution: 2.946 Å

PDB-8ev7:
Crystal structure of the Thermus thermophilus 70S ribosome in complex with kanamycin, mRNA, and A-, P-, and E-site tRNAs
Method: X-RAY DIFFRACTION / Resolution: 2.89 Å

Chemicals

ChemComp-MG:
Unknown entry

ChemComp-AKN:
(2S)-N-[(1R,2S,3S,4R,5S)-4-[(2R,3R,4S,5S,6R)-6-(aminomethyl)-3,4,5-tris(oxidanyl)oxan-2-yl]oxy-5-azanyl-2-[(2S,3R,4S,5S / medication, antibiotic*YM / Amikacin

ChemComp-ZN:
Unknown entry

ChemComp-SF4:
IRON/SULFUR CLUSTER / Iron–sulfur cluster

ChemComp-HOH:
WATER / Water

ChemComp-KAN:
KANAMYCIN A / antibiotic*YM / Kanamycin A

ChemComp-PHE:
PHENYLALANINE / Phenylalanine

Source
  • escherichia coli (E. coli)
  • escherichia phage t4 (virus)
  • thermus thermophilus hb8 (bacteria)
KeywordsRIBOSOME / Amikacin / antibiotic / aminoglycoside / 70S ribosome / inhibitor / tRNA / Kanamycin / cryo-EM

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