A novel approach for
identifying how chemicals in the environment - called environmental
estrogens - can produce infertility, abnormal reproductive development,
including "precocious puberty," and promote breast cancer has been developed by breast cancer researchers from the Florida campus of The Scripps
Research Institute (TSRI).
Environmental estrogens work by binding to the estrogen receptor, a
protein in cells that guides sexual maturation and reproduction. The new
research shows how high-resolution imaging techniques could give
scientists a window into how exposure to these chemicals may impact
‘High-resolution imaging techniques could give scientists a window into how exposure to environmental estrogens may impact public health.’
This research method could also be used to speed up the discovery of
new drugs for breast cancer and many other diseases, added study senior
author Kendall Nettles, associate professor at TSRI.
The study was published online ahead of print in the journal Cell Chemical Biology
Taking Snapshots of a Crucial Receptor
Environmental estrogens control the estrogen receptor's activity by
changing its shape, which can mimic the effects of estrogen. These
chemicals can also block receptor activity, as seen with the breast
cancer therapy tamoxifen.
These changes are often exceedingly small, in the sub-ångström range
(one ångström is equal to one ten-billionth of a meter). In fact,
changes to even a single atom in a chemical or endocrine therapy drug
can often drive widely divergent outcomes, but the resolution of the
typical crystal structure does not allow visualization of these small
Nettles calls the approach in the new study "super-resolution x-ray crystallography."
X-ray crystallography is a technique that produces a snapshot of the
receptor's 3-D atomic structure. Like the images produced by
photography or microscopy, x-ray crystal structures have a certain
resolution, or level of detail, that can be visualized. With optical
microscopy, super-resolution imaging - a discovery for which researchers
were awarded the Nobel Prize in 2014 - can be achieved by combining many
images to produce a sharper picture.
Nettles and his colleagues reasoned that they could use a similar
approach with x-ray crystallography to compare molecular snapshots, or
structures, and better understand how estrogenic chemicals control
Developing a Framework for Drug Design
They found that by combining data about structural disturbances from
many structures with activity profiles of their ligands (the estrogenic
chemicals), researchers can identify the sub-ångström details that
determine endocrine disruption.
"Our novel approach offers a framework for understanding the diverse
effects of environmental estrogens and other endocrine disruptors,
furthering efforts to develop improved breast cancer therapies," said
TSRI Research Associate Jerome C. Nwachukwu, first author of the study.
"This approach can also be applied to other allosteric receptors."
Super-resolution x-ray crystallography can also be applied to the
large groups of receptors that comprise the targets for most known
drugs. With structure-based drug design, chemists can use this new
approach to visualize how to modify drug-candidate chemicals to promote
the desirable therapeutic profile.