The Oxazolidinone Antibiotics Perturb the Ribosomal Peptidyl-transferase Center and Effect TRNA Positioning

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2008 Sep 2

PMID 18757750

Citations 119

Authors

Daniel N Wilson

Frank Schluenzen

Joerg M Harms

Agata L Starosta

Sean R Connell

Paola Fucini

Affiliations

Soon will be listed here.

Abstract

The oxazolidinones represent the first new class of antibiotics to enter into clinical usage within the past 30 years, but their binding site and mechanism of action has not been fully characterized. We have determined the crystal structure of the oxazolidinone linezolid bound to the Deinococcus radiodurans 50S ribosomal subunit. Linezolid binds in the A site pocket at the peptidyltransferase center of the ribosome overlapping the aminoacyl moiety of an A-site bound tRNA as well as many clinically important antibiotics. Binding of linezolid stabilizes a distinct conformation of the universally conserved 23S rRNA nucleotide U2585 that would be nonproductive for peptide bond formation. In conjunction with available biochemical data, we present a model whereby oxazolidinones impart their inhibitory effect by perturbing the correct positioning of tRNAs on the ribosome.

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