One-Pot Total Synthesis of a Post-translationally Modified Max Transcription Factor Sheds Light on Ser-Phosphorylation and Lys-Acetylation Crosstalk in DNA Binding

We report a one-pot total synthesis of the transcription factor Max in seven consecutive steps, starting from three peptide segments and employing native chemical ligation. The developed synthesis facilitates the generation of homogeneous Max analogues bearing defined transformations within hours in excellent yields, enabling us to probe the effect of the crosstalk between Ser-phosphorylation and Lys-acetylation on the Max function. Our findings reveal that these post-translational modifications significantly inhibit DNA-binding activity, potentially by disrupting essential Max-DNA interactions.