The Fic protein Doc uses an inverted substrate to phosphorylate and inactivate EF-Tu

Daniel Castro-Roa, Abel Garcia Pino, Steven De Gieter, Nico Van Nuland, Remy Loris, Nikolay Zenkin

Research output: Contribution to journalArticlepeer-review

130 Citations (Scopus)


Fic proteins are ubiquitous in all of the domains of life and have critical roles in multiple cellular processes through AMPylation of (transfer of AMP to) target proteins. Doc from the doc-phd toxin-antitoxin module is a member of the Fic family and inhibits bacterial translation by an unknown mechanism. Here we show that, in contrast to having AMPylating activity, Doc is a new type of kinase that inhibits bacterial translation by phosphorylating the conserved threonine (Thr382) of the translation elongation factor EF-Tu, rendering EF-Tu unable to bind aminoacylated tRNAs. We provide evidence that EF-Tu phosphorylation diverged from AMPylation by antiparallel binding of the NTP relative to the catalytic residues of the conserved Fic catalytic core of Doc. The results bring insights into the mechanism and role of phosphorylation of EF-Tu in bacterial physiology as well as represent an example of the catalytic plasticity of enzymes and a mechanism for the evolution of new enzymatic activities.
Original languageEnglish
Pages (from-to)811-817
Number of pages7
JournalNat. Chem. Biol.
Publication statusPublished - 2013


  • Structural biology
  • Toxin-antitoxin module
  • Fic protein
  • Doc protein
  • Elongation factor Tu


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