Argonne's Structural Biology Center first to produce 1,000
structures that improve understanding of human and environmental
health
ARGONNE, Ill. (Jan. 27, 2006) — Researchers at the Structural
Biology Center (SBC) at the U.S. Department of Energy's Argonne National Laboratory have contributed
their 1,000th structure to the Protein
Data Bank. The data bank houses the
molecular structures of all proteins characterized so far and makes them available
to researchers worldwide to study.
This structure – and its 999 predecessors determined with data obtained at
Argonne's SBC – provides important pieces to the puzzle of understanding human
and environmental health by imaging the molecules that control and regulate
it.
The 1,000th deposit is a three-dimensional structure of thrombospondin-1 that
provides insight into how cells sense and communicate information about their
health and how that information triggers cell responses ranging from raising
defenses to fight disease and other perceived threats to cell death.
Thrombospondins are a family of extracellular glycoproteins that regulate
cellular behavior during tissue genesis and repair such as wound healing. These
functions are mediated by its interaction with a proteins and proteoglycans
in the extracellular environment and at the cell surface.
The research was published in Structure (2006
Jan. 14 (1): 33-42), and is a collaboration between the Dana
Farber Cancer Institute of Harvard
Medical School and Argonne's SBC.
"SBC has been a pioneer of protein structure determination at the APS
and worldwide," said Argonne's Associate Laboratory Director for Scientific
User Facilities Murray Gibson. "This is a marvelous achievement."
Some of the structures have revealed how proteins are synthesized inside the
cell (ribosome), how we see light (rhodopsin), how cells communicate (integrin)
and how cells differentiate (gene regulatory factors). Other findings have
shed insight into origins of diseases including cancer, diabetes, osteoporosis,
and infections by human pathogens causing staph, anthrax and other infectious
diseases.
Among the characterized proteins are 280 related to human disease — including
cancer, the deadly anthrax bacterium and the common cold virus — 150 from human
pathogens and 210 more with biotechnological applications that will contribute
to increased productivity, new biomedical tests and applications.
"This is the first time any center has produced so many structures," said
Argonne's Director of the SBC Andrzej Joachimiak. "When you consider it
took six years (starting in 1972) to deposit the first 37 structures into the
Protein Data Bank, you see how technology has advanced for SBC users to have
deposited 1,000 structures in six years."
"One of the challenges facing structural biologists and indeed much of
biology has been the slow pace, often measured in months or years, of determining
the structures of biomolecules that are important for advances in energy, health
and the environment," said Ari Patrinos, DOE associate director of science
for biological and environmental research.
"This achievement represents an important step to narrow the gap between
the current pace of gene discovery and the ability of scientists to have access
to new information on the functions of those genes," Patrinos said. "This
Department of Energy-funded user facility continues to find ways for scientists
to further speed the process of protein structure determination."
DOE's Office
of Biological and Environmental Research provided the SBC's construction
funding and provides annual support for operation and equipment.
The SBC at Argonne, which has been providing data since 1998, is based at
the Advanced Photon Source, this hemisphere's most brilliant source of X-rays
for research. The center is a major macromolecular crystallography research
facility, and provides two experimental stations and a laboratory for researchers
from universities, other national laboratories and industry. Structure data
is analyzed – a process that early on took months – and later deposited to
the Protein Data Bank.
At the Advanced Photon Source, brilliant X-ray beams travel around a ring
two-thirds of a mile in circumference – about the size of Chicago's Wrigley
Field. The SBC operates two of the 70 available X-ray beamlines located around
that ring. In research stations on those beamlines, X-rays pass though a rotating,
tiny crystal of biological molecules. The scattering pattern is captured by
a large digital camera. Researchers using computers and advanced software calculate
the position of the atoms in the crystal, revealing its three-dimensional structure.
The structure provides insight into how the biomolecule performs its task.
For example, biologists determined how bacteria communicate by a mechanism
called quorum sensing using the TraR protein to activate genes of an agricultural
pathogen that causes tumors in plants. Bacteria release and sense chemical
signals known as pheromones. The pheromones are embedded within the protein
until amino acids critical to gene copying are released into the butterfly-shaped
body of TraR. This information may be used to manipulate this communication
to aid helpful bacteria or thwart harmful bacteria.
The SBC at Argonne has been home to the world's most productive structural
biology beamline since 1998. Joachimiak credits the high productivity, quality
and efficiency to the powerful X-rays beams at the APS and advances in technology,
automation and software. "They allow us to deliver the greatest detail
to scientists, and to do it quickly and efficiently," he said.
"It is also a reflection of the quality of the scientific team that Joachimiak
has assembled," said Argonne Biosciences Director Lee Makowski. "These
scientists are available around the clock to help visiting scientists from
all over the world to collect data from their protein crystals."
The powerful X-ray beams provide very fast data collection. Entire data sets
can be captured in minutes compared to hours and days at other facilities.
The SBC provides such a high level of detail and resolution that individual
atoms can be observed.
Colleagues Wladek Minor at the University
of Virginia and Zbyszek Otwinowski
at the University
of Texas Southwestern
Medical Center worked with SBC operators
to automate the many computer steps needed to convert X-ray diffractions images
of the protein crystal into a 3-D image – cutting the solution time from months
to minutes.
Argonne SBC staff are continually making improvements. Nearly two-thirds of
the 1,000 structures have been determined in the past three years. "We
are committed," said Joachimiak, "to modernize the facility and expand
its capabilities to maintain its leadership in structural biology for the community."
The SBC is a user facility supported by DOE's Office
of Science; researchers
are chosen through a peer-reviewed proposal process and come from DOE, the
National Institutes of Health, the National
Science Foundation, universities
and industry. — Evelyn Brown
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