|Scientists Unveil Structure of Molecular Target
of Many Drugs
More than 40 years after beta blockers were first used clinically,
scientists can finally get a close-up look at the drugs' molecular
target-the β2-adrenergic receptor. The
work is particularly exciting because it offers the first glimpse
into an important, but scientifically elusive family of human proteins
called G protein-coupled receptors (GPCRs).
Because GPCRs control critical bodily functions, several of our
senses, and the action of about half of today's pharmaceuticals,
the research promises not only to speed the discovery of new and
improved drugs, but also to broaden our understanding of human
health and disease.
Published online in the October 25 issue of Science Express,
the research was supported by two major initiatives of the National
Institutes of Health-the Roadmap and the Protein Structure Initiative
(PSI), which is led by the National Institute of General Medical
Sciences. Additional funding came from the National Institute of
Neurological Disorders and Stroke.
The work represents a technical tour de force that required the
scientists to devise several new techniques. Many of the difficulties
arose because the receptor is a membrane protein-one of the trickiest
molecules to capture in three-dimensional detail. The only other
known GPCR structure comes from a cow and was determined in 2000.
"Because of their role in so many medically important processes
and the great challenges they present for detailed study, membrane
proteins have been one focus of the NIH Roadmap for Medical Research," said
NIH Director Elias A. Zerhouni, M.D. "The determination of
this structure is an exciting example of the rewards of the Roadmap
After considerable efforts with the protein in a natural form,
the researchers, led by Raymond Stevens of The Scripps Research
Institute and Brian Kobilka of Stanford University, turned to protein
engineering. To overcome problems with the protein's floppiness,
they replaced part of the protein with another, stiffer molecule,
essentially clamping the protein into place so they could work
with it more easily. They also utilized several new methods to
minimize the amount of the protein needed for detailed structural
"This is an absolutely remarkable advance," said Jeremy
M. Berg, Ph.D., director of NIGMS which, in addition to spearheading
the PSI, plays a leading role in the membrane protein Roadmap initiative. "Many
laboratories around the world are trying to reveal the secrets
of these proteins and this new structure takes this field to a
To learn more about the NIH Roadmap for Medical Research, visit <http://nihroadmap.nih.gov/>.
Details about the Protein Structure Initiative are available at <http://www.nigms.nih.gov/Initiatives/PSI/>.
For additional information, contact the NIGMS Office of Communications
and Public Liaison at 301-496-7301.
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Human Services. It is the primary federal agency for conducting
and supporting basic, clinical and translational medical research,
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