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Species-specific antibiotic-ribosome interactions: implications for drug development

MPS-Authors
http://pubman.mpdl.mpg.de/cone/persons/resource/persons50642

Wilson,  Daniel N.
Dept. of Vertebrate Genomics (Head: Hans Lehrach), Max Planck Institute for Molecular Genetics, Max Planck Society;

Harms,  Jörg M.
Max Planck Society;

http://pubman.mpdl.mpg.de/cone/persons/resource/persons50444

Nierhaus,  Knud H.
Ribosomes, Max Planck Institute for Molecular Genetics, Max Planck Society;

Schlünzen,  Frank
Max Planck Society;

http://pubman.mpdl.mpg.de/cone/persons/resource/persons50160

Fucini,  Paola
Ribosomes, Max Planck Institute for Molecular Genetics, Max Planck Society;

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Citation

Wilson, D. N., Harms, J. M., Nierhaus, K. H., Schlünzen, F., & Fucini, P. (2005). Species-specific antibiotic-ribosome interactions: implications for drug development. Biological Chemistry Hoppe-Seyler (Berlin), 386(12), 1239-1252. doi:10.1515/BC.2005.141.


Cite as: http://hdl.handle.net/11858/00-001M-0000-0010-8548-5
Abstract
In the cell, the protein synthetic machinery is a highly complex apparatus that offers many potential sites for functional interference and therefore represents a major target for antibiotics. The recent plethora of crystal structures of ribosomal subunits in complex with various antibiotics has provided unparalleled insight into their mode of interaction and inhibition. However, differences in the conformation, orientation and position of some of these drugs bound to ribosomal subunits of Deinococcus radiodurans (D50S) compared to Haloarcula marismortui (H50S) have raised questions regarding the species specificity of binding. Revisiting the structural data for the bacterial D50S-antibiotic complexes reveals that the mode of binding of the macrolides, ketolides, streptogramins and lincosamides is generally similar to that observed in the archaeal H50S structures. However, small discrepancies are observed, predominantly resulting from species-specific differences in the ribosomal proteins and rRNA constituting the drug-binding sites. Understanding how these small alterations at the binding site influence interaction with the drug will be essential for rational design of more potent inhibitors.