Using some of the most powerful nuclear magnetic resonance
equipment available, researchers at the University
of California, Davis, are making discoveries about the shape
and structure of biological molecules—potentially leading to new ways to treat
or prevent diseases such as breast cancer and Alzheimer’s disease.
The findings appear in Nature
and Journal of Biological Chemistry.
“These are exquisite three-dimensional objects, and the
structures really give insight into how they function in the cell,” chemistry
professor James Ames
Two recently published studies show what the campus can do
with its 800-MHz nuclear magnetic resonance spectrometer, acquired with grant
support from the National Science Foundation.
In a paper published online by Nature, Ames and colleagues at the University of Toronto and the
University of Cambridge, England, offer insight into the hot topic of calcium
channels, linked to Parkinson’s and Alzheimer’s diseases, among other things.
The researchers described the workings of two protein
channels that are similar in structure and function. Inositol triphosphate is
the “key” that unlocks the inositol triphosphate receptor, opening a gateway
that releases calcium inside the cell. The ryanodine receptor does the same
thing when it binds another molecule, ryanodine.
The new 3D view shows that although the sequences of these
proteins are different, their structures at the “receptor end” are very
“They are basically superimposable,” Ames said. They are also interchangeable—if
the “receptor end” of one is grafted to the “calcium channel end” of the other,
the receptor still functions.
Researchers hope that understanding how inositol
triphosphate triggers calcium flows, and how that process might be boosted or
blocked, will lead to new ways to treat neurodegenerative diseases.
Calcium also features in a paper published in the Journal of Biological Chemistry. Ames, David Sacks at the
National Institutes of Health, and their colleagues show how a molecule called
calmodulin, which is sensitive to calcium, interacts with the estrogen
When activated with the right amount of calcium, one
calmodulin protein attaches to two estrogen receptors and draws them into a
bear hug. That structure, or dimer, is then sensitive to the estrogen’s
attaching to another part of the molecule. In the right amounts, the
combination of estrogen, calmodulin and calcium allows the estrogen receptor to
attach to DNA and turn particular genes on or off.
The structure also reveals how calmodulin stops the estrogen
receptor from being broken down and removed. Another protein, ubiquitin, is
responsible for attaching to proteins inside cells and flagging them for
disposal. Calmodulin blocks those parts of the estrogen receptor where
ubiquitin can attach. That could result in a buildup of estrogen receptors—which
is associated with tumor formation, Ames
X-ray crystallography at the University
of Toronto figured in the inositol
triphosphate receptor work, while Ames’
team used the 800-MHz nuclear MRI to work on the inositol triphosphate receptor
and the calmodulin/estrogen receptor. Similar to the MRI machines used in
hospitals, nuclear magnetic resonance spectroscopy provides information about
both the structure of molecules and how atoms are moving within them.