the Estrogen Receptor
Ifeoma Archimalo '18
is a common drug used to treat the symptoms of menopause,
such as hot flashes. It functions by increasing the amount of
estrogen in the body, activating transcription of the estrogen
nuclear receptors. However, by increasing the expression of ER, it
puts the user at increased risk of developing breast, ovarian, and
uterine cancer (where expression of estrogen increases
proliferation of mammary cells and possibility of malignant cell
encodes for estrogen
receptor-alpha, one of the two nuclear receptors that mediates
the action of 17B-estradiol (E2). Transcriptional activation of the
receptor involves the action of two distinct activation functions,
AF1 and AF2, located in the N-terminal. When a ligand, such as E2,
binds the receptor undergoes a conformational change, facilitating
the recruitment of co-activators and the direct binding to cis-acting
In this conformation of ER-alpha, the nuclear receptor is a
complex of three receptors (homo trimer) and was triple mutated. At
three sites--Cys-381, Cys-417, and Cys-530--cysteine was changed to
By changing these amino acid, a partial agonism structure of ER-alpha
was back generated, and the position of helix H12 is at the heart of
II. Estrogen Receptor
ER-alpha belongs to the family of nuclear receptors. All
members of this family are composed of six domains (A-F). The E
region of the ER receptor is the ligand binding domain (LBD), which
contains AF-2, a ligand-dependent transactivation factor.
Structurally, the LBD is composed primarily of alpha helix folds.
The estrogen receptor belongs to the class of steroid nuclear
receptors, which require a ligand to stabilize the receptor and
control gene expression.When the receptor is ligand-bound, it will
move from the cytoplasm to the nucleus, the receptor will form a
dimer, with if then able to bind to DNA of estrogen response
elements.The ligand-receptor complex will then be
able to recruit other proteins needed for transcription.
In many cancers, especially of the breast, the relative
expression of the receptor is determined and utilized by oncologists
to guide their treatment of a patient's specific cancer. Most breast
cancer cells are considered ER+, meaning they have an ER expression
>50% (determined by immunohistochemistry). With an increased
expression of ER, proliferation of mammary cells increases,
increasing cell division and DNA replication (and thus the chances
of mutation) and disrupting apoptosis. Thus when a patient is
diagnosed as ER+, oncologists will prescribe drugs. like tamoxifen,
which act as estrogen and bond to ER, but will reduce change ints
conformation to inactivate transcription, hindering the expression
of estrogen nuclear receptors
III. Helix H12
The primary component
of the ER receptor that determines whether transcription will occur
is the helix H12
. This helix carries AF2, an activation function.
In the antagonist position (transcriptionally inactive)
conformation, a ligand is not bound to the nuclear receptor and the
helix is exposed to the solvent and the receptor is unstable. The
antagonist position of H12 is not unique.
In the agonist position, ligand binding is present and
triggers H12 to reposition on the core of the ligand binding domain,
much like a lid closing the ligand pocket.
When the ER-alpha receptor was triple mutated (C381S, C417S,
C530S) the H12
helix (highlighted in red) moved from the agonist position to
the antagonist position, despite the presence of ligand binding,
creating a partial agonism structure
IV. Estradiol Binding
Estradiol is a
ligand that binds to the ER receptor, changing its conformation
and activating transcription. The ligand interacts with His-524
through the 17B-hydroxyl
. Then His-524 then forms a hydrogen bond with the peptidic carbonyl
group of Glu-419 in the loop 6-7
. Glu-419 forms a hydrogen bond network with Glu-339 of helix H3 and
Lys-531 of helix H11
. This network favors the proper position of helix H12, into the
In addition, ligand binding,
faciliates the activation of AF2, the ligand dependent
V. Tamoxifen Binding
is structurally similar to estradiol and its other derivatives.
Therefore it is able to interact and bind to the same binding sites of
the ER receptor. However, the result of tamoxifen binding varies
greatly from that estradiol, and in actuality has a range of effects.
It may simply inactive the receptor, but it may also activate it, but
interacts with other proteins and DNA. It has also been observed that
when tamoxifen is bound, H12 remains in an antagonist position,
keeping the transcription levels low. Regardless of the mechanism,
tamoxifen inhibits the growth of cancer cells, and is therefore used
widely in the clinical treatment of breast and uterine cancers.
Krust, Coralie Fontaine, Anne Abot, Gilles Flouriot, Celine
Toutain, Hortense Berges, Alain-Pierre Gadeau, Francoise
Lenfant, Pierre Gourdy ,Pierre Chambon, and Jean-Francois Arnal.
"Activation Function (AF2) of Estrogen Receptor-alpha Is
Required for the Atheroprotective Action of Estradiol but Not to
Accelerate Endothelial Healing." Proceedings
of the National Academy of Sciences of the United States of
America. National Academy of Sciences, 25 July
Gangloff, M., Ruff, M., Eller, S., Duclaud, S.,
Wurtz, J.M., and Moras, D. 2001. Crystal
Structure of a Mutant hERalpha Ligand-Binding Domain Reveals Key
Structural Features for the Mechanism for Partial Agonism.
J.Biol.Chem. 276: 15059
David S. "The Molecular Perspective: Tamoxifen and the Estrogen
Receptor." The Oncologist:
Fundamentals of Cancer Medicine." April 2002.
Hall, Julie M., John H. Couse, and Kenneth S. Korach. "The
Multifaceted Mechanisms of Estradiol and Estrogen Receptor
Signaling." The Journal of
Biological Chemistry, 17 July 2001.