Identification of a peptide motif that potently inhibits two functionally distinct subunits of Shiga toxin.

Shiga toxin (Stx) is a major virulence factor of enterohemorrhagic Escherichia coli, which causes fatal systemic complications. Here, we identified a tetravalent peptide that inhibited Stx by targeting its receptor-binding, B-subunit pentamer through a multivalent interaction. A monomeric peptide with the same motif, however, did not bind to the B-subunit pentamer. Instead, the monomer inhibited cytotoxicity with remarkable potency by binding to the catalytic A-subunit. An X-ray crystal structure analysis to 1.6 Å resolution revealed that the monomeric peptide fully occupied the catalytic cavity, interacting with Glu167 and Arg170, both of which are essential for catalytic activity. Thus, the peptide motif demonstrated potent inhibition of two functionally distinct subunits of Stx. Watanabe-Takahashi, Tamada, Senda et al. identify a tetravalent peptide that inhibits Shiga toxin (Stx), a major virulence factor of enterohemorrhagic Escherichia coli, by targeting its receptor-binding. On the other hand, a monomeric peptide containing the same motif occupies the Stx catalytic cavity, suggesting that this peptide motif can inhibit two subunits of Stx. [ABSTRACT FROM AUTHOR]