Abstract
The ERα transcription factor that induces tumor growth is a potential target for breast cancer treatment. Each monomer of the ERα DNA-binding domain (ERαDBD) homodimer has two conserved (Cys)(4)-type zinc fingers, ZF1 (N-terminal) and ZF2 (C-terminal). Electrophilic agents release Zn(2+) by oxidizing the coordinating Cys of the more labile ZF2 to inhibit dimerization and DNA binding. Microsecond-length molecular dynamics (MD) simulations show that greater flexibility of ZF2 in the ERαDBD monomer leaves its Cys more solvent accessible and less shielded from electrophilic attack by sulfur-centered hydrogen bonds than ZF1 which is buried in the protein. In the unreactive DNA-bound dimer, the formation of the dimer interface between the highly flexible D-box motif of ZF2 decreases the solvent accessibility of its Cys toward electrophiles and increases the populations of sulfur-containing hydrogen bonds that reduce their nucleophilicity. Examination of these factors in ERαDBD and other proteins with labile ZF motifs may reveal new targets to treat viral infections and cancer.