Mutations to transcription factor MAX allosterically increase DNA selectivity by altering folding and binding pathways.

ABSTRACT: Understanding how proteins discriminate between preferred and non-preferred ligands ('selectivity') is essential for predicting biological function and a central goal of protein engineering efforts, yet the biophysical mechanisms underpinning selectivity remain poorly understood. Towards this end, we study how variants of the promiscuous transcription factor (TF) MAX (H. sapiens) alter DNA specificity and selectivity, yielding >1700 K_ds and >500 rate constants in complex with multiple DNA sequences. Twenty-two of the 240 assayed MAX point mutations enhance selectivity, yet none of these mutations occur at residues that contact nucleotides in published structures. By applying thermodynamic and kinetic models to these results and previous observations for the highly similar yet fa

SUBMITTER: Hastings R 

PROVIDER: S-EPMC11729911 | biostudies-literature | 2025 Jan

REPOSITORIES: biostudies-literature