This binding induces conformations in the activation loop of MARK2 that resemble closely that seen in the active state for most protein kinases, even though no nucleotide is present in the active site or phosphorylation in the activation loop. The CagA peptide, therefore, appears to function as a substrate analog that traps the kinase in a state that resembles the activated form, but which is incapable of any kinase activity. Our data indicate that the peptide is both necessary and sufficient for inhibition of the MARK2 kinase activity, and that key, conserved amino acids in the PAR1 family substrates found in CagA are required for this inhibition as well.