Alterations at the peptidyl transferase centre of the ribosome induced by the synergistic action of the streptogramins d
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BioMed Central
Open Access
Research article
Alterations at the peptidyl transferase centre of the ribosome induced by the synergistic action of the streptogramins dalfopristin and quinupristin Jörg M Harms†1, Frank Schlünzen*†1,2, Paola Fucini2, Heike Bartels1 and Ada Yonath1,3 Address: 1Max-Planck Research Unit for Ribosomal Structure, 22603 Hamburg, Germany, 2Max-Planck-Institute for Molecular Genetics, 14195 Berlin, Germany and 3Weizmann Institute, 76100 Rehovot, Israel Email: Jörg M Harms - [email protected]; Frank Schlünzen* - [email protected]; Paola Fucini - [email protected]; Heike Bartels - [email protected]; Ada Yonath - [email protected] * Corresponding author †Equal contributors
Published: 01 April 2004 BMC Biology 2004, 2:4
Received: 22 January 2004 Accepted: 01 April 2004
This article is available from: http://www.biomedcentral.com/1741-7007/2/4 © 2004 Harms et al; licensee BioMed Central Ltd. This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original URL.
Abstract Background: The bacterial ribosome is a primary target of several classes of antibiotics. Investigation of the structure of the ribosomal subunits in complex with different antibiotics can reveal the mode of inhibition of ribosomal protein synthesis. Analysis of the interactions between antibiotics and the ribosome permits investigation of the specific effect of modifications leading to antimicrobial resistances. Streptogramins are unique among the ribosome-targeting antibiotics because they consist of two components, streptogramins A and B, which act synergistically. Each compound alone exhibits a weak bacteriostatic activity, whereas the combination can act bactericidal. The streptogramins A display a prolonged activity that even persists after removal of the drug. However, the mode of activity of the streptogramins has not yet been fully elucidated, despite a plethora of biochemical and structural data. Results: The investigation of the crystal structure of the 50S ribosomal subunit from Deinococcus radiodurans in complex with the clinically relevant streptogramins quinupristin and dalfopristin reveals their unique inhibitory mechanism. Quinupristin, a streptogramin B compound, binds in the ribosomal exit tunnel in a similar manner and position as the macrolides, suggesting a similar inhibitory mechanism, namely blockage of the ribosomal tunnel. Dalfopristin, the corresponding streptogramin A compound, binds close to quinupristin directly within the peptidyl transferase centre affecting both A- and P-site occupation by tRNA molecules. Conclusions: The crystal structure indicates that the synergistic effect derives from direct interaction between both compounds and shared contacts with a single nucleotide, A2062. Upon binding of the streptogramins, the peptidyl transferase centre undergoes a significant conformational transition, which leads to a stable, non-productive orientat
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