Data-driven modeling of estrogen receptor

The National Institute of General Medical Sciences awarded Case Western Reserve University $431,750 on May 1, 2026, under the Biomedical Research and Research Training program (CFDA 93.859) to support data-driven structural characterization of the estrogen receptor and its domain interactions relevant to breast cancer therapeutics.

The research comprises two integrated projects. Project 1 will characterize the structural properties of the estrogen receptor's N-terminal transactivation domain through nuclear magnetic resonance spectroscopy and small-angle X-ray scattering, generating comprehensive structural insights. Project 2 will examine dynamic interactions between the DNA-binding domain and ligand-binding domain using cryo-electron microscopy combined with solution-state small-angle X-ray scattering analysis to reveal how various factors influence domain communication. The work will establish a detailed framework for understanding estrogen receptor regulation in normal and disease states with implications for the broader nuclear receptor family. Computational analysis of the resulting data will illuminate molecular mechanisms underlying receptor function and methodological advances applicable to protein dynamics and domain interactions across the receptor family, potentially informing innovative therapeutic strategies for hormone-dependent cancers.

Work is performed at Case Western Reserve University's Office of Research Administration in affiliation with University Hospitals of Cleveland in Cleveland, Ohio. The period of performance runs through February 28, 2031.

Abstract

The estrogen receptor (ER or ERΑ) plays a fundamental role in breast cancer through complex molecular mechanisms involving its n-terminal transactivation domain (NTD), DNA-binding domain (DBD), and ligand- binding domain (LBD). Understanding their structural dynamics is crucial for developing next-generation ER- targeted therapeutics. Our research employs advanced biophysical techniques to decode two fundamental aspects of ER regulation. Project-1 will characterize the structural properties of the NTD through nuclear magnetic resonance spectroscopy and small-angle x-RAY scattering (saxs), generating comprehensive structural insights. Project-2 will examine the dynamic interactions between DBD and LBD using cryo-electron microscopy combined with solution-state saxs analysis, revealing how various factors influence domain communication. These studies will establish a detailed framework for understanding ER regulation in normal and disease states, with broad implications for the nuclear receptor family. Our data-driven computational strategy will illuminate new molecular mechanisms underlying receptor function. The methodological advances from this research will enhance our understanding of protein dynamics and domain interactions across the nuclear receptor family, potentially leading to innovative therapeutic strategies for hormone-dependent cancers.