Exotoxin A–eEF2 complex structure indicates ADP ribosylation by ribosome mimicry

René Jørgensen, A. Rod Merrill (), Susan P. Yates, Victor E. Marquez, Adrian L. Schwan, Thomas Boesen and Gregers R. Andersen ()
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René Jørgensen: University of Aarhus
A. Rod Merrill: Department of Molecular and Cellular Biology
Susan P. Yates: Department of Molecular and Cellular Biology
Victor E. Marquez: National Cancer Institute at Frederick, NIH
Adrian L. Schwan: University of Guelph
Thomas Boesen: University of Aarhus
Gregers R. Andersen: University of Aarhus

Nature, 2005, vol. 436, issue 7053, 979-984

Abstract: Abstract The bacteria causing diphtheria, whooping cough, cholera and other diseases secrete mono-ADP-ribosylating toxins that modify intracellular proteins. Here, we describe four structures of a catalytically active complex between a fragment of Pseudomonas aeruginosa exotoxin A (ETA) and its protein substrate, translation elongation factor 2 (eEF2). The target residue in eEF2, diphthamide (a modified histidine), spans across a cleft and faces the two phosphates and a ribose of the non-hydrolysable NAD+ analogue, βTAD. This suggests that the diphthamide is involved in triggering NAD+ cleavage and interacting with the proposed oxacarbenium intermediate during the nucleophilic substitution reaction, explaining the requirement of diphthamide for ADP ribosylation. Diphtheria toxin may recognize eEF2 in a manner similar to ETA. Notably, the toxin-bound βTAD phosphates mimic the phosphate backbone of two nucleotides in a conformational switch of 18S rRNA, thereby achieving universal recognition of eEF2 by ETA.

Date: 2005
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DOI: 10.1038/nature03871

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