Determination of Structural Factors Contributing to Protection of Zinc Fingers in Estrogen Receptor α through Molecular Dynamic Simulations

Authors

Patricia B. Lutz, Regent University
Wesley R. Coombs, Regent University
Craig A. Bayse, Old Dominion UniversityFollow

Document Type

Article

Publication Date

2025

DOI

10.1021/acs.jpcb.4c05730

Publication Title

The Journal of Physical Chemistry B

Volume

129

Issue

8

Pages

2226-2234

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 Zn²⁺ 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.

Rights

© 2025 The Authors.

This article is licensed under a Creative Commons Attribution 4.0 (CC BY 4.0) International License.

Original Publication Citation

Lutz, P. B., Coombs, W. R., & Bayse, C. A. (2025). Determination of structural factors contributing to protection of zinc fingers in estrogen receptor α through molecular dynamic simulations. The Journal of Physical Chemistry B, 129(8), 2226-2234. https://doi.org/10.1021/acs.jpcb.4c05730

ORCID

0000-0002-3490-576X (Bayse)

Repository Citation

Lutz, Patricia B.; Coombs, Wesley R.; and Bayse, Craig A., "Determination of Structural Factors Contributing to Protection of Zinc Fingers in Estrogen Receptor α through Molecular Dynamic Simulations" (2025). Chemistry & Biochemistry Faculty Publications. 345.
https://digitalcommons.odu.edu/chemistry_fac_pubs/345