Fig. 1

Catalytic mechanism, architecture, key functional sites, and disease-causing missense mutations of KMD6A. a Domain structure and the schematic of its catalytic mechanism. Relative positions of KDM6A Kabuki variants identified from the patients are highlighted in red on top of the domain diagram. b The catalytic domain structure of KDM6A in complex with the H3K27me3 peptide, metal ions and the cofactor 2OG (PDB access code 3AVR). The catalytic domain is composed of the jumonji domain flanked by two additional sub-domains and a long flexible linker. The bound substrate is shown as ball-and-sticks while the catalytic domain is shown as ribbons. The color codes are identical to the ones used in Fig. 1A. (c–e) Zoomed views of the active site, substrate binding interface, and the zinc ion binding site. two damaging control residues are labeled in red. H3 histone residues are labeled in orange. f Mapping of Kabuki syndrome missense variants onto its molecular structure. None of the Kabuki variants are found right at the critical molecular interaction sites. Figures were made using PyMOL (The PyMOL Molecular Graphics System Version 2.3.0., Schrödinger, LLC)