Preliminary Molecular Dynamic Simulations of the Estrogen Receptor Alpha Ligand Binding Domain from Antagonist to Apo

T Dwight Mcgee,Jesse Edwards,Adrian E Roitberg

doi:10.3390/ijerph5020111

Abstract

Estrogen receptors (ER) are known as nuclear receptors. They exist in the cytoplasm of human cells and serves as a DNA binding transcription factor that regulates gene expression. However the estrogen receptor also has additional functions independent of DNA binding. The human estrogen receptor comes in two forms, alpha and beta. This work focuses on the alpha form of the estrogen receptor. The ERalpha is found in breast cancer cells, ovarian stroma cells, endometrium, and the hypothalamus. It has been suggested that exposure to DDE, a metabolite of DDT, and other pesticides causes conformational changes in the estrogen receptor. Before examining these factors, this work examines the protein unfolding from the antagonist form found in the 3ERT PDB crystal structure. The 3ERT PDB crystal structure has the estrogen receptor bound to the cancer drug 4-hydroxytamoxifen. The 4-hydroxytamoxifen ligand was extracted before the simulation, resulting in new conformational freedom due to absence of van der Waals contacts between the ligand and the receptor. The conformational changes that result expose the binding clef of the co peptide beside Helix 12 of the receptor forming an apo conformation. Two key conformations in the loops at either end of the H12 are produced resulting in the antagonist to apo conformation transformation. The results were produced over a 42ns Molecular Dynamics simulation using the AMBER FF99SB force field.

Highlights

The structure and chemistry of the estrogen receptor has been of extreme research focus for several years, due to the receptors role as a DNA binding transcription factor, which regulates gene expression
In previous work, simulations were only about 5ns for any estrogen receptor. This is not long enough to see the extent of dynamics that are present in our simulation
The molecular dynamics results here show that van der Waals interactions with the complexed ligand are necessary to hold the ERα ligand binding domain (LBD) in the antagonist position

Summary

Introduction

The structure and chemistry of the estrogen receptor has been of extreme research focus for several years, due to the receptors role as a DNA binding transcription factor, which regulates gene expression. [1] in recent years there have been growing apprehensions about environmental chemicals that disrupt oestrogenic signaling and negatively affect reproduction in humans and in wildlife [1] Both forms of estrogen have been linked to these types of problems. We use the 3ERT PDB structure [2, 3] in the antagonist form, extract the ligand, and run MD simulations to watch the ER unfold into a conformation similar to the agonist structure This conformational change is important due to ER implications in cancer research, birth defects [3], and potential deleterious effects to the ER from exposure to pesticides [4]

Methods

Results

Conclusion