Fig. 4: Cryo-EM structure of human 15-PGDH in complex with NADH and SW222746.
From: Small molecule inhibitors of 15-PGDH exploit a physiologic induced-fit closing system
a The chemical structure of SW222746. b The cryo-EM electron density map of the 15-PGDH-NADH-SW222746 complex, with each protomer in the homodimeric assembly differentially colored. SW222746 and NADH are displayed in light blue and orange respectively. c Zoom-in view of the drug binding pocket of SW222746 (cyan). Residues forming the drug-binding pocket are color-coded in three groups those in the catalytic core (magenta), those around the catalytic core (blue), and those forming a lid to the pocket (light blue). Hydrogen bonds are shown. d 2D schematic of contacts between inhibitor SW222746 and 15-PGDH. The color code for residue is the same as c. e Decomposition of relative energetic contributions of individual 15-PGDH residues to SW222746 binding as calculated by MM-PBSA. Relative binding energies are presented as mean values ±SEM calculated from 15,000 evenly distributed snapshots from MD simulations.
