Figure 4.

Example of bulky PP1-like inhibitors interacting with the small gatekeeper in TgCDPK1. A) 3-BrB-PP1 interacting with TgCPDK1, which has a Gly gatekeeper (PDB: 3MA6) creating a deep hydrophobic pocket that the 3-bromo-benzyl ring points backward into. (B) Superposition of 3-BrB-PP1 from Fig. 4A on the structure of mutant TgCDPK1(G128M) shows steric clash with Met gatekeeper. (C) Compounds that inhibit CDPKs with small gatekeepers are derivatives of pyrazolopyrimidines, acylbenzimidazoles, 5-aminopyrazole-4-carboxamide and imidazopyridazines. The substituent mostly likely to occupy the hydrophobic pocket next to the small gatekeeper is denoted as R₁ in each case.