Human estrogen receptor

Supervisor: J.J.M. Vervoort - Proteins@Work group

General Project Description

Introduction

Estrogens are a family of steroid hormones that are predominantly produced in the reproductive organs of the human body. After being secreted, they are delivered throughout the body in the blood within seconds, directing the growth of the human body from child to adulthood. Estrogens are essential elements to stimulate cells growth either in the foetus, puberty or in adult life. Estrogens act on a wide range of target tissues, such as breast, uterus, brain, bone, liver, and heart, playing a critical role in the physiology of the female reproductive system, the maintenance of bone density, and cardiovascular health. Lack of estrogens can lead to osteoporosis in women and bone loss in aging men. However, the stimulation of cell proliferation in the breast and the uterus can increase a woman's risk of developing breast and uterus cancer.

The biological effects of estrogens are mediated by the estrogen receptor (ER), a ligand-activated transcription factor belonging to the super family of the nuclear receptors. Estrogen receptors, which are distributed in the estrogen target tissues, are found in two isoforms: the classical subtype alpha estrogen receptor (ERa) and the recently discovered subtype beta estrogen receptor (ERß). These two receptors share common structural and functional domains. The amino acid sequence identity is 96% in their DNA-binding domains, and 58% in the ligand-binding domains, which determines their similar binding manners to estrogen response elements (EREs) on the DNA and binding affinities to estrogenic ligands. More than 150 natural and man-made ligands can bind to ERa and ERß with different binding affinities for the two protein isoforms and with different biological activity.

Student Project

Computational studies on binding affinities of estrogenic compounds to estrogen receptors. The computational study develops a proportional relationship between the known target biological property and the corresponding calculated explanatory data. The biological data for a target may be the binding constant (Ki), IC50 or EC50 values. The binding affinity is predicted based upon 3D structural information and physical-chemical properties of protein-ligand interaction. These properties are obtained from molecular dynamics simulations of protein-ligand in a solvent shell as well as molecular orbital calculations.

Figure 1. Protein-ligand interaction site.

The assembly of macromolecular ER-protein complexes under the influence of ligands can be measured using an immunoprecipitation pull down assay coupled to high-resolution mass spectrometry measurements. The biological effect of the binding of ligands to the receptor can be measured in HEK cells in which the specific expression of ERa or the ERb protein is coupled to a luciferase reporter assay.