Figure 1.
Schematic representation of DNMT1 and 3s.
NLS, nuclear localization signal; RFD, replication foci-targeting sequence; BAH, bromo-adjacent homology domain; TRD, target recognition domain; PWWP, a conserved region containing the core tetrapeptide of ‘proline-tryptophan-tryptophan-proline’; ATRX, cys-rich region. Interaction domains of HDAC1, HDAC2, and the DNMT3s are indicated. The methyltransferase domain comprising six most conserved motifs is enlarged.
Figure 2.
Chemical structures of DNMT inhibitors.
Figure 3.
Workflow of the docking study using induced-fit docking and multiple receptor conformations.
Figure 4.
Comparison of the structures of DNMT1 and DNMT3A.
(A) Structure alignment of MTase with other domains of DNMT1 and DNMT3A. The BAH1, BAH2, CXXC, autoinhibitory linker, TRD region and MTase domain of DNMT1 are colored in blue, orange, red, yellow and pink, respectively. The MTase domain of DNMT3A is colored in green and bound SAH is in space fill representation. (B) Sequence alignment of MTase domain of DNMT1 and DNMT3A. Weak-to-identical sequence similarities are colored in hues graded from light blue to dark blue. Identical residues interacting with ligands have been indicated with dots. Red cylinder and blue arrows represent helices and β-strands, respectively.
Figure 5.
Induced-fit docking results of (A) SAH (carbon atoms in black), (B) SGI-1027 (carbon atoms in green), and (C) CBC12 (carbon atoms in orange) in the MTase domain of DNMT3A.
Comparison of the interaction diagram (D) between SAH and SGI-1027, and (E) CBC12. Acidic, hydrophobic, basic, polar, and other residues at the active site are represented by red, green, purple, blue, and gray spheres, respectively. Hydrogen bonds between the ligand and backbone or side chains are shown in solid or dashed pink lines.
Table 1.
Summary of induced-fit docking results of SGI-1027 and CBC12 into the MTase domain of DNMT1 and DNMT3A with/without other domains.
Figure 6.
Structure alignment of MTase domain of DNMT1 (pink ribbon) and DNMT3A (green ribbon) after induced-fit docking.
The binding sites of SGI-1027 in DNMT1 and DNMT3A are represented by pink and green mesh, respectively. Comparison of the side chain conformations between DNNT1 and DNMT3A in the substrate and cofactor binding sites is shown in the enlarged box. The amino acid residues of DNMT1 (carbon atoms in pink) and DNMT3A (carbon atoms in green) are indicated with a red and black number, respectively.
Figure 7.
Induced-fit docking results of (A) SAH (carbon atoms in black), (B) SGI-1027 (carbon atoms in green), and (C) CBC12 (carbon atoms in orange) with the MTase domain of DNMT1.
TRD region is represented by yellow loop. Comparison of the interaction diagram (D) between SAH and SGI-1027, and (E) CBC12. Acidic, hydrophobic, basic, polar, and other residues at the active site are represented by red, green, purple, blue, and gray spheres, respectively. Hydrogen bonds between the ligand and backbone or side chains are shown in solid or dashed pink lines.
Figure 8.
Induced-fit docking results of (A) SAH (carbon atoms in black), (B) SGI-1027 (carbon atoms in green), and (C) CBC12 (carbon atoms in orange) in the MTase domain of DNMT1 in the presence of other domains.
TRD region and autoinhibitory linker are represented by yellow and red loop, respectively. Comparison of the interaction diagram (D) between SAH and SGI-1027, and (E) CBC12. Acidic, hydrophobic, basic, polar, and other residues at the active site are represented by red, green, purple, blue, and gray spheres, respectively. Hydrogen bonds between the ligand and backbone or side chains are shown in solid or dashed pink lines. The π-cation interactions are indicated with orange lines.
Table 2.
XP scores of regular docking, induced-fit docking and ensemble docking of SGI-1027 and CBC12 into the MTase domain of DNMT1 and DNMT3A with/without other domains.
Figure 9.
Proposed inhibitory mechanism of SGI-1027 in DNMT1.