Extended Data Figure 3: Structure of ADD–CD–C^DNMT3L in autoinhibitory form.

a, Superimposition of human ADD–CD–C^DNMT3L with mouse CD^Dnmt3a-C^Dnmt3L (lack of ADD domain, PDB accession number 2QRV)²² structures shown in ribbon representations. CD–C^DNMT3L in two structures is well aligned with a root mean squared deviation of 1.28 Å for 723 Cα aligned. The function of DNMT3A–DNMT3L complex dimerization has been characterized in a previous study²². The functions and structures of the CD and C^DNMT3L domains, and the CD–CD and CD–C^DNMT3L interfaces, were not discussed in this work. b, Overall structure of ADD–CD–C^DNMT3L with CD–C^DNMT3L shown in electrostatic potential surface, and the ADD domain and linker shown in ribbon representation. The linker packs against a hydrophobic surface of the CD domain. c, d, Close-up view of linker-CD (c) and ADD–CD (d) interfaces with the electrostatic potential surface of the CD domain indicated. Critical residues are shown in stick representation. e, Superimposition of ADD–CD–C^DNMT3L and DNMT3L-H3 structures (PDB accession number 2PVC)¹⁵ shown in ribbon representations in two different views. The CD domain and C-like domain of DNMT3L were aligned for comparison. Note that the extended loop of the ADD domain in ADD–CD–C^DNMT3L overlaps with an α helix in the DNMT3L–H3 structure. DNMT3L is unlikely to adopt a similar conformation to that of ADD–CD–C^DNMT3L because otherwise the ADD domain will have steric hindrance with the C-like domain of DNMT3L (dashed circle). According to the above analyses, the structure of the autoinhibitory form of DNMT3A could not be predicted on the basis of the DNMT3L structure because the overall structures of DNMT3A and DNMT3L are different.