Figure 5: Comparison of MPP8 chromodomain structures bound with hDNMT3AK47me2 and H3K9me3 peptides.

(a) Binding specificity of hDNMT3AK47me2 peptide by MPP8. Stick model showing the hDNMT3A peptide (green), residues 39–50 (out of the residues 39–53 used for crystallization). The side chains of resides 39, 40 and 50 were modelled as alanines, whereas residues 51–53 were disordered. The MPP8 chromodomain contacts the eight residues (P41–V48) of the hDNMT3A peptide via hydrogen bonds (dashed lines) and van der Waals contact with P41, A45 and V48 (shown, respectively, in space-filling model). (b) Superimposition of hDNMT3AK47me2 peptide (green) and H3K9me3 peptide (orange) bound with MPP8 chromodomain (derived from PDB 3QO2 (ref. 44)). The conformations of the conserved TARK tetrapeptide sequence overlaps well in the two structures, whereas the residues away from the conserved sequence adopt different conformations. The largest difference lies in the N-terminal residues of bound hDNMT3 with a bent conformation at P41–S42, whereas the H3 peptide exhibited an extended conformation. (c) Superimposition of MPP8-hDNMT3AK47me2 structure (protein in grey and peptide in green) with that of MPP8-H3K9me3 (orange). The pairwise root-mean-square-deviation between the two structures is ∼0.6 Å (54 pairs of main-chain atoms). The MPP8 loop between helices αA and αB undergoes a concerted movement (as indicated by a red arrow) along with the different peptide conformations observed in panel b. The loop includes residue Asp98 interacting with S42 of hDNMT3A (see panel a). The β strands are labelled by numbers. (d) Omit electron density, 2Fo–Fc, contour at 1σ above the mean, is superimposed with the refined K47me2 peptide.