FIGURE 1.

PPM1D phosphatase is allosterically inhibited by the capped amino acid (CAA) compounds, but the precise binding site is unknown. (A) The capped amino acid compounds have a common amino acid-like substructure, and small differences in their chemical structure (i.e., the absence of a carbonyl) can contribute to very large differences in their potency. (B) The AlphaFold-predicted structure of PPM1D highlights key regions that have been implicated in the binding of the capped amino acid compounds. The active site is shown in salmon sticks while two residues identified as proximal to the binding site based on photolabeling experiments are shown in blue sticks. The flap domain, a region hypothesized to be the primary CAA compound binding site, is shown in cyan. Another region hypothesized to be the primary CAA compound binding site, the hinge, is shown in orange.