of Estrogen Related Receptor Gamma
in complex with Bisphenol
Ian Richardson and Myles Alderman
(ERRγ) is a nuclear
the breast and bone. Despite
sharing structural homology with
Estrogen Receptor family
of proteins, ERRs do not bind estrogen and
thus allow for transcription regulation by small lipophilic molecules
which can act as agonists
or inverse agonists.
Bisphenol A (BPA) is an agonist for ERRγ and is falsly
recognized as estrogen by the protein. Since BPA mimics the
hormone, it is very tightly bound by ERRγ and thereby
ensures the continuous activation of the protein. This
control over ERRγ has led
studies suggesting that
BPA increases the risk of breast cancer and may
be associated with a variety of health problems.
(4-hyrdoxytamoxifen) is an antagonist to the ERR family of proteins.
Tamoxifen is useful because it blocks estrogen from the
cancer cells via competitive antagonism, and since some breast cancers
require estrogen to grow, it thereby inhibits cancer growth.
It is commonly perscribed as hormone therapy for recovering breast
four chemically identical polypeptide subunits
each with 456 amino
acids, and these combine to form two homodimers. Helicies
9-10 appear to be important in dimerization.
has its own ligand binding domain (LBD)
and binding of a ligand
LBD of one unit does not affect the binding affinity of any of the
other LBDs in the protein. With a volume of 280 cubic
LBD of ERRγ is extremely
small - the LBD volume of classic Estrogen Receptors is much larger at
370 cubic Angstroms.
the small size of
ERRγ's LBD, and the
that it is largely composed of hydrophobic
ERRγ's LBD, and the
fact that it is largely composed of hydrophobic residues
provides a favorable environment for small, hydrophobic molecules.
Thus the phenyl rings and methyl groups of BPA
are strongly bound to the LBD of ERRγ.
conserved portions of the DNA binding domain
(DBD) and the ligand
explain why the ERR family of proteins are constituitively active.
The core DBD
is composed of two zinc
specialized folds in the protein which are stabilized by two
zinc atoms embedded in the protein
. This core DBD is
composed of an alpha helix
that rests in the major
groove of the DNA. Sequence specific
interactions with DNA occur via H-bonds with Lys-128, Lys-124, and
Since the ERR family of
proteins binds to DNA as a monomer, it is neccesary to have additional
contact with the DNA to ensure sequence specific binding. The
result is a unique feature in the ERR family: the C-terminal extension
The CTE provides an AT-hook motif that allows sequence
specific binding with the minor groove of the DNA, adjacent to the DBD.
Additional H-bonds are formed with the CTE and the DNA with
Arg-179, Gly-180, Arg-182
Once both the DBD and the CTE have been bound to DNA, a
hydrophobic interaction occurs between Tyr-185 of the CTE and Leu-169
and Val-117 of the DBD
. It is thought that this
interaction stabilizes and combines the interactions of the DBD and the
Bisphenol A Binding
BPA - the highest of any phenol/polyphenol tested.
is a small ligand and fits tightly
in the LBD of ERRγ
between ERRγ and
BPA arise from a set of Pi stacking and hydrogen
stacking occurs between the ligand and residues Tyr-326 and Phe-435
There are additional
hydrophobic interactions between the phenol rings of BPA and the
hydrophobic carbon side chains of Leu-342 and Leu-345
Hydrogen bonding occurs
between BPA and Glu-275, Arg-316, Tyr-326, and Asn-346
hydrogen bond with Tyr-326 is enabled by a hydrogen bond between
Tyr-326 and Asn-346 that pulls the Tyr-326 residue close enough to BPA
to enable an interaction between them
is an effective breast cancer
drug which works via competitive
in Estrogen Receptor Alpha (ERα),
but it binds much tighter to ERRγ. The variation in
binding affinity is due to structural differences between
and ERα. The most significant difference in the
binding pocket is the
Phe-435 residue in ERRγ
which corrosponds to
Leu-525 in ERα.
difference in amino acids is the primary reason that estrogen cannot
bind to ERRγ, the steric strain from the PHE prevents it.
interactions between Tamoxifen and ERRγ are
primarily of three
Glu-275, and Arg-316
bonds with the ligand.
binding interactions between
Tamoxifen and ERRγ are
by the prominent hyrophobic residues seen earlier in the LBD.
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receptor γ in the presence of phenol derivative compounds."
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Micah D., Signe M.A. Holmbeck, Ronald M. Evans, H.Jane Dyson, and Peter
E. Wright. "Monomeric Complex of Human Orphan Estrogen Related
Receptor-2 with DNA: A Pseudo-dimer Interface Mediates Extended
Half-site Recognition." Journal of Molecular Biology 327.4 (2003):
Wang, Liping, et al. "X-ray crystal
structures of the estrogen-related
receptor-γ ligand binding domain in three functional states
reveal the molecular basis of small molecule regulation." Journal of
Biological Chemistry 281.49 (2006): 37773-37781.