Three-dimensional modeling of c-AID mutations in specific genes from DT-AID mice that recapitulate tumor driver mutations in humans. Structural analyses using available crystal structures of the proteins mutated by AID shared between humans and mice. c-AID mutations of humans/mice in tumor cells. (A) Illustration of PIM-1 PDB 3A99⁵⁶  with a red-to-blue color ramp indicating N- to C-terminal sense. Substrates, ATP, and peptide (in sticks) are bound in the active site and labeled for reference. Key residues are labeled, including the mutated Ser₉₇ (in spheres) at the C-terminal end of helix αC. (B) MCL-1 PDB 5W89,⁵⁷  shown with similar structure representation and color ramp as in panel A. A synthetic peptide (purple sticks) that acts as MCL-1 antagonist is bound in the MCL-1 hydrophobic groove. The position of Ser₂₈₅, substituted by an Asn in the mouse model, is highlighted. (C) Using the crystal structure of a full nucleosome (PDB 4QLC) that includes linker histone H5,⁵⁸  homologous linker histone H1.3 PDB 1GHC⁵⁹  was superposed onto H5 and is illustrated in the top complex with H1.3 colored with a ramp. The accuracy of the superposition was aided by structurally aligning an independent complex of H1 with an entire nucleosome PDB 5NL0,⁶⁰  not shown here for clarity. The position of Ser₉₀ in H1.3 is highlighted in the inset, pointing toward the nucleosomal DNA. Below the inset, Ser₉₀ was substituted in silico by an asparagine to model the c-AID mutation found on H1.3. (D) c-AID mutations found at identical positions in histone H1.4 (human) and its ortholog Hist2h2aa1 (mouse). For all illustrations (A-D), the codon context of key mutations in both species is shown in the bottom with homologous residues aligned and the specific c-AID mutation boxed. Blue boxes mark c-AID mutations conserved in both human and mouse, but encoding different amino acid changes. Red boxes mark c-AID mutations that result in identical amino acid substitutions. The c-AID signature context (C>T/G within RCY motifs) is highlighted in green in mice and in human species.