Fig. 6: Schematic illustrating the proposed mode of action involving 15-PGDH inhibition.
From: Small molecule inhibitors of 15-PGDH exploit a physiologic induced-fit closing system
(+)-SW209415 and SW222746 inhibitors possess different chemical groups that each specifically recognize the catalytic core of 15-PGDH. Binding of inhibitor substituents (triangle) to the catalytic center (S138 and Y151) positions the inhibitor within the enzyme. Binding of either inhibitor then induces a hydrophobic collapse of residues that form the lid (yellow) of the enzyme binding site to fully encapsulate the inhibitors in the protein binding pocket. The conserved F185 and Y217 residues reside at either end of the 15-PGDH lid and form interactions with other inhibitor substituents (green ball) to maintain the lid in the closed position.
