Structural basis for aminoglycoside inhibition of bacterial ribosome recycling.
Aminoglycosides are widely used antibiotics that cause messenger RNA decoding errors, block mRNA and transfer RNA translocation, and inhibit ribosome recycling. Ribosome recycling follows the termination of protein synthesis and is aided by ribosome recycling factor (RRF) in bacteria. The molecular mechanism by which aminoglycosides inhibit ribosome recycling is unknown. Here we show in X-ray crystal structures of the Escherichia coli 70S ribosome that RRF binding causes RNA helix H69 of the large ribosomal subunit, which is crucial for subunit association, to swing away from the subunit interface. Aminoglycosides bind to H69 and completely restore the contacts between ribosomal subunits that are disrupted by RRF. These results provide a structural explanation for aminoglycoside inhibition of ribosome recycling.
Physical Biosciences Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA.
Maria A
MA
Borovinskaya
Raj D
RD
Pai
Wen
W
Zhang
Barbara S
BS
Schuwirth
James M
JM
Holton
Go
G
Hirokawa
Hideko
H
Kaji
Akira
A
Kaji
Jamie H Doudna
JH
Cate
D000617:Aminoglycosides / Q000737:chemistry* / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D018360:Crystallography, X-Ray; D004926:Escherichia coli / Q000187:drug effects* / Q000235:genetics; D005839:Gentamicins / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D015394:Molecular Structure; D009355:Neomycin / Q000737:chemistry / Q000494:pharmacology; D010303:Paromomycin / Q000737:chemistry / Q000494:pharmacology; D021122:Protein Subunits / Q000737:chemistry; D012269:Ribosomal Proteins / Q000737:chemistry*; D012270:Ribosomes / Q000737:chemistry*; D013329:Structure-Activity Relationship
D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D005839:Gentamicins; D021122:Protein Subunits; D012269:Ribosomal Proteins; C087267:ribosome releasing factor; D010303:Paromomycin; D009355:Neomycin