Elongation factor SelB is responsible for cotranslational incorporation of the 21(st) amino acid selenocysteine (Sec) into proteins. UGA stop codon is recoded as a Sec codon in presence of a downstream mRNA hairpin. Prokaryotic SelB has EF-Tu-like N-terminal domains and a C-terminal extension containing four tandem winged-helix motifs (WH1-4). The C-terminal extension recognizes the mRNA hairpin. Crystal structures of the Escherichia coli WH3/4 domains and WH1-4 domains from Moorella thermoacetica each bound to mRNA were determined. These structures provide insights into how the molecular switch that may allow communication between tRNA and mRNA binding sites is formed and illustrate how RNA acts as an activator of the switch. The structures show that tandem WH motifs not only provide an excellent scaffold for RNA binding but can also have an active role in the function of protein-RNA complexes.