(A)
Reversible, mixed-type PAD4 inhibitors. Kis is the dissociation constant for the enzyme–inhibitor
complex. (B) Crystal structure of PAD4 bound to inhibitor 9, GSK199 (PDB code 4X8G). GSK199 (gray) directly interacts with active site residues H471
and D473, and is further stabilized by binding to F634 and N588. Hydrogen
bonds of <3.5 Å are represented as dashed black lines. (C)
The image on the left side depicts the structure of PAD4 (orange)
bound to inhibitor GSK199 (gray, PDB code 4X8G) superimposed onto the structure of PAD4
(green) bound to BAA substrate (green stick model, PDB code 1WDA). Residues 633–640
(red, denoted by α) of PAD4 bound to BAA adopt an α-helical
conformation, while residues 633–645 (yellow, denoted by β)
of PAD4 bound to GSK199 form an antiparallel β-sheet. The image
on the right side compares the binding sites of BAA (green) and GSK199
(gray) mapped onto the structure of PAD4 (PDB code 1WDA), colored according
to its electrostatic surface potential.