Modeling of KMT2D domain structures and comparison with the mutated domain structures. (A) Schematic overview of the predictive value of intrinsically disordered regions in KMT2D. The KMT2D gene is aligned with the PONDR (Predictor of Naturally Disordered Regions) chart to visualize mutations that lie in the predicted disordered region. (B) The domain structure of PHD₇ of KMT2D^wt was generated by Phyre2. The schematic display of Arg residues (cyan) are represented in the stick structures near PHD₇ of KMT2D^mut at the respective positions R5153P and R5154Q (cyan), the latter having been identified in T-ALL (red). (C) The crystal structure of the FYR domain, superimposition of Phrye2 depiction of the KMT2D (magenta), FYRN (pink), and FYRC (orange) motifs with the crystal structure of the TBRG1 motif (PDB: 2WZO).⁴⁵  The residues forming the core hydrophobic pocket (yellow) are shown with stick structures and display of the Ileu5232 (cyan) in the FYRN motif. (D) The mutation Ileu5232Val (cyan) leads to loss of CH3, which could result in destabilizing of the domain. (E) Crystal structure of KMT2D SET domain (PDB: 4Z4P).⁴⁶  The mutation Ser5476 (cyan) is located near the SAM binding cleft (SAH is modeled) and makes direct contact with a water molecule that supports Cys5532 (yellow, stick structure) located in the post-SET loop involved in zinc binding (purple). (F) The Ser5476Pro mutation impairs water binding, which could destabilize the Cys-zinc interaction required for proper folding.