Figure 5: Structural basis underlying the pharmacologic–phylogenetic Ce-2 macrocycle series-iPGM orthologue relationship.
(a) Relationship between Ce-2 macrocycle truncation series IC50s and iPGM orthologues. Analogues with no detectable inhibitory activity are indicated as inactive. Data represent mean±s.d. values of the log normal distributed IC50s determined for the given peptide for experiments with ≥4 replicates; otherwise error bar is determined from the nonlinear fit of the standard Hill equation to the aggregated data from the replicates. Values are from Supplementary Table 3 converted from pIC50 where \({\rm IC}_{{\rm 50}} = 10^{{\rm - pIC}_{50} } \). (b) Select amino-acid sequence alignment of iPGM orthologues in this study (see Supplementary Fig. 10 for full alignment). iPGM residues within 5 Å of Ce-2d are coloured orange. Residues identical between C. elegans and E. coli iPGM are coloured yellow; grey indicated hinge regions; green and blue are amino acids that ligand metal ions. (c) Cavity formed from C. elegans iPGM residues (light blue chain under transparent spheres) within 5 Å of the Ce-2d macrocycle shown as a worm α-chain (gold) representation scaled by B-factor with select side chains (Tyr3, Pro4, thioether linkage, and C-terminal Tyr11 amide) shown. The iPGM Ala334 residue is shown as a CPK space fill. Electrostatic surface of the Ce-2d binding cavity is also shown.
