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LCLS offers new method for examining membrane proteins

By R&D Editors | March 14, 2012

Lipidic Sponge Phase

Scientists embedded tiny protein crystals in an oily solution that mimics the supportive environment of the cell membrane, and then squirted them through a microjet into the path of a powerful X-ray laser. By analyzing the diffraction patterns made by X-rays scattering off the crystals, they were able to determine the protein’s structure. A key challenge was adjusting the viscosity of the oily solution, called a “lipidic sponge phase,” so it wouldn’t clog the microjet’s nozzle, shown here. Image: Richard Neutze

Many membrane proteins serve as gateways in
and out of the cell. Because they act as “traffic control” for infectious
agents and disease-fighting drugs, they are the targets of more than 60% of all
drugs on the market. Yet of the estimated 30,000 membrane proteins in the human
body, scientists understand the detailed structures of only 18.

Now experiments at SLAC National
Accelerator Laboratory’s
Linac Coherent Light Source (LCLS) have shown a promising new way to collect
data on these elusive proteins. Researchers embedded tiny protein crystals in
an oily paste that mimics the supportive environment of the cell membrane, and
then hit them with a powerful X-ray laser to determine the protein’s structure.
They reported their results in Nature
Methods
.

Until now, drug design based on membrane
protein structures has been difficult; it simply took too much time and money
to crystallize and probe the finicky proteins, which become unstable when taken
out of their lipid environment, said Richard Neutze of the University of Gothenburg
in Sweden,
a co-author of the study. “The chances of failure are so high,” he said, adding
that the new method “could help us increase knowledge about how the body
functions and who we are as humans.”

Earlier studies at the LCLS determined that
tiny protein crystals could be used to analyze the rough molecular structure of
an important membrane protein complex called Photosystem I. Since these small
crystals are much easier to prepare than the big ones required by traditional
methods, the technique opened the door to understanding tens of thousands of
proteins that were previously out of reach. Scientists squirted a solution
containing the tiny crystals into the path of the X-ray laser beam. X-rays
scattering off electrons in the protein’s atoms formed diffraction patterns
that could be used to determine the protein structure.

Researchers have also achieved good results
with very challenging membrane proteins by embedding them in a fatty paste
before crystallization.

Scientists wondered whether that approach
would work for experiments at the LCLS. Since the nozzle that squirts samples
into the path of the X-ray laser has a very small opening, getting the
viscosity of the paste just right would be a challenge: If it’s too thick, it
will not form a thin enough jet, and may even clog the nozzle.

In this experiment, researchers mixed the
membrane protein—a photosynthetic reaction center found in some bacteria—with a
lipid called monoolein that had been thinned with water, and then added
crystallization agents. After filtering out the largest crystals, they injected
the liquid suspension, known as a “lipidic sponge phase,” through a microjet
across the X-ray laser beam. They recorded 365,035 images in less than two
hours, and analyzed 265 diffraction patterns to determine the protein’s
structure.

This particular experiment was carried out
on a protein whose structure was already known in great detail. It mapped the
protein with a resolution of 8.2 A, compared to less than 2 A in previous,
high-resolution studies. Nevertheless, it demonstrates that the method works
and sets the stage for more detailed studies at the LCLS.

LCLS has already made available shorter
wavelengths of X-rays and doubled the rate at which X-ray laser pulses can hit
samples, from 60 to 120 pulses per second. Neutze said he expects these
developments will soon make it possible to get high-resolution structures for
membrane proteins, giving researchers a powerful tool for understanding at a
molecular level why people become ill and what can be done to treat them. The
work also has implications for energy research, since scientists are trying to
reverse-engineer the photosynthetic processes that plants use to harvest energy
from the sun, which takes place in membrane protein complexes.

The
team’s next goal is to collect the approximately 10,000 diffraction images they
estimate are needed to make high-resolution maps of protein structure. This
first step in successfully collecting 265 images bodes well for future
applications, the paper concludes.

SOURCE

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