Fig. 4: The PWWP- and ADD-mediated intramolecular interactions constitute two distinct layers of autoinhibition.
From: Structural insight into hierarchical DNMT3A autoinhibition and its dysregulation in disease
a Structure of the 3A-1 subunit in the DNMT3A2-DNMT3L complex, highlighting the H3K36me2- and H3K4me0-binding sites located at two separate domain interfaces of DNMT3A. The key residues involved in occluding the histone-binding sites are shown in stick representations. b Close-up view of the structural overlay between DNMT3A2-DNMT3L and the H3K4me0-bound DNMT3A ADD (PDB 4QBQ), with the conformational shift of ADD D529, D531 and E545 indicated by red arrow in the expanded views. PWWP G332 and H3 R8 involved in steric clashes are shown in sphere representation. c Close-up view of the structural overlay between DNMT3A2-DNMT3L and the H3K36me3-binding DNMT3B PWWP (PDB 5CIU), highlighting the competing interaction between PWWP-H3K36me3 and PWWP-ADD. d In vitro DNA methylation assay of DNMT3A2-DNMT3L, WT or mutant, on the nucleosome substrates with various histone modifications. The statistical analysis used two-tailed Student’s t test. Data are mean ± s.d. (n = 3 biological repeats). Source data are provided as a Source Data file.
