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J. Biol. Chem., Vol. 279, Issue 44, 45919-45925, October 29, 2004

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Crystal Structure of ADP-ribosylated Ribosomal Translocase from Saccharomyces cerevisiae^*

René Jørgensen, Susan P. Yates¶||, David J. Teal¶||, Jakob Nilsson, Gerry A. Prentice¶, A. Rod Merrill¶||**, and Gregers Rom Andersen

From the Macromolecular Crystallography, Department of Molecular Biology, University of Aarhus, Gustav Wieds vej 10C, DK8000 Aarhus, Denmark and the ^¶Biochemistry Group, Department of Microbiology, University of Guelph, Guelph, Ontario N1G 2W1, Canada

The crystal structure of ADP-ribosylated yeast elongation factor 2 in the presence of sordarin and GDP has been determined at 2.6 Å resolution. The diphthamide at the tip of domain IV, which is the target for diphtheria toxin and Pseudomonas aeruginosa exotoxin A, contains a covalently attached ADP-ribose that functions as a very potent inhibitor of the factor. We have obtained an electron density map of ADP-ribosylated translation factor 2 revealing both the ADP-ribosylation and the diphthamide. This is the first structure showing the conformation of an ADP-ribosylated residue and confirms the inversion of configuration at the glycosidic linkage. Binding experiments show that the ADP-ribosylation has limited effect on nucleotide binding affinity, on ribosome binding, and on association with exotoxin A. These results provide insight to the inhibitory mechanism and suggest that inhibition may be caused by erroneous interaction of the translation factor with the codon-anticodon area in the P-site of the ribosome.

Received for publication, June 4, 2004 , and in revised form, August 12, 2004.

^* 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.

The atomic coordinates and structure factors (code 1U2R) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

Supported by Merck Research Laboratories, the Danish Science Research Council, Human Frontier Science Program, and the European Union.

^|| Supported by the Canadian Institutes of Health Research and the Canadian Cystic Fibrosis Research Foundation.

^** To whom correspondence may be addressed. Tel.: 519-824-4120 (ext. 53806); Fax: 519-837-1802; E-mail: rmerrill{at}uoguelph.ca. To whom correspondence may be addressed. Tel.: 45-89425024; Fax: 45-86123178; E-mail: grand{at}bioxray.dk.

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