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J. Biol. Chem., Vol. 282, Issue 1, 657-666, January 5, 2007

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Sordarin Derivatives Induce a Novel Conformation of the Yeast Ribosome Translocation Factor eEF2^*

Rikke Søe, Ralph T. Mosley, Michael Justice^¶, Jennifer Nielsen-Kahn^¶, Mythili Shastry^¶, A. Rod Merrill^||1, and Gregers R. Andersen²

From the Centre for Structural Biology, Department of Molecular Biology, University of Aarhus, DK-8000 Aarhus C, Denmark, the Departments of Medicinal Chemistry and ^¶Infectious Diseases, Merck Research Laboratories, Rahway, New Jersey 07065, and the ^||Department of Molecular and Cellular Biology, University of Guelph, Guelph, Ontario N1G 2W1, Canada

The sordarins are fungal specific inhibitors of the translation factor eEF2, which catalyzes the translocation of tRNA and mRNA after peptide bond formation. We have determined the crystal structures of eEF2 in complex with two novel sordarin derivatives. In both structures, the three domains of eEF2 that form the ligand-binding pocket are oriented in a different manner relative to the rest of eEF2 compared with our previous structure of eEF2 in complex with the parent natural product sordarin. Yeast eEF2 is also shown to bind adenylic nucleotides, which can be displaced by sordarin, suggesting that ADP or ATP also bind to the three C-terminal domains of eEF2. Fusidic acid is a universal inhibitor of translation that targets EF-G or eEF2 and is widely used as an antibiotic against Gram-positive bacteria. Based on mutations conferring resistance to fusidic acid, cryo-EM reconstructions, and x-ray structures of eEF2, EF-G, and an EF-G homolog, we suggest that the conformation of EF-G stalled on the 70 S ribosome by fusidic acid is similar to that of eEF2 trapped on the 80 S ribosome by sordarin.

Received for publication, August 16, 2006 , and in revised form, November 2, 2006.

The atomic coordinates and structure factors (code 2NPF and 2E1R) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by Canadian Institutes of Health Research and Canadian Cystic Fibrosis Foundation.

² Supported by the Danish Science Research Council, DANSYNC, the European Union Framework Program 5, and Merck Research Laboratories. To whom correspondence should be addressed: Dept. of Molecular Biology, University of Aarhus, Gustav Wieds Vej 10C, DK-8000 Aarhus C, Denmark. Tel.: 45-89425024; Fax: 45-86123178; E-mail: gra{at}mb.au.dk.

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