Scientists Unveil Structure Of Molecular Target Of Many Drugs

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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 b2-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.

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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 investment."

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 studies.

"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 new level."

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