Fig. 2: Sulphostin inhibits DPP proteins by a covalent binding mode.
From: Sulphostin-inspired N-phosphonopiperidones as selective covalent DPP8 and DPP9 inhibitors
a X-ray crystal structure of Sulphostin in complex with DPP9 refined to a final resolution of 1.89 Å. The phosphosulfamate group is covalently bound to the catalytically active serine S730 residue and is contoured at 1 σ with the refined 2Fo-Fc electron density map. Hydrogen bond interactions are depicted as dashed lines. b X-ray crystal structure of Sulphostin in complex with DPP4 refined to a final resolution of 2.38 Å. The phosphosulfamate group is covalently bound to S630 and is contoured at 1 σ with the refined 2Fo-Fc electron density map. Hydrogen bond interactions are depicted as dashed lines. c X-ray crystal structure of Sulphostin in complex with the S730A-DPP9 mutant (1.89 Å resolution) showing the non-covalent interactions prior to the covalent bond formation. The ligand is superimposed with the refined 2Fo-Fc electron density map contoured at 1 σ. Hydrogen bond interactions are depicted as dashed lines. d Sulphostin is coordinated by E248 and E249 from the EE helix with the free N-terminus of the (S)−3-aminopiperidine-2-one, which occupies two substrate binding sub-sites. e The proposed general binding mechanism of Sulphostin with DPP proteins. The stereogenic phosphorus of Sulphostin is attacked by the serine of the catalytic triad, whereby the (S)−3-aminopiperidin-2-one moiety functions as a leaving group.
