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San Diego Scientists Uncover Structure Of Key Proteins Targeted By Half Of Medications

Probes, shown glowing here, revealed the inner architecture of the protein A2...

Credit: Matthew Eddy and Kurt Wüthrich/ Scripps Research Institute

Above: Probes, shown glowing here, revealed the inner architecture of the protein A2aAR in the new study.

A study led by The Scripps Research Institute uncovered more details about the structure of key proteins targeted by nearly half of medications, which could help with future drug development, the La Jolla-based organization reported on Thursday.

The scientists used a special imaging system to view the A2A adenosine receptor protein at work, where before they could only see static models. They likened the discovery, published in the journal Cell, to having once been able to only view a car, but now being able to see its engine.

The protein is part of the G-protein-coupled receptor family, which is targeted by roughly 40 percent of all approved pharmaceuticals, according to TSRI.

"This basic knowledge is potentially helpful for improving drug design,'' said Kurt Wuthrich, a TSRI professor of structural biology and senior author of the study. "GPCRs do just about everything you can imagine, but for a long time, drug design was being done without knowing how GPCRs looked.''

The A2A adenosine receptor is one of more than 800 proteins residing in the plasma membrane and is responsible for blood flow and inflammation. It also mediates the effects of caffeine.

The receptor is also used to treat Parkinson's disease and a relatively new target for cancer therapies.

Before, scientists had a basic idea of how its structure in active and inactive states. Wuthrich and his team used nuclear magnetic resonance to see how they bind with prospective medications, and give scientists clues into how they could manipulate the process.

Wuthrich won a Nobel Prize for chemistry in 2002 for pioneering work with the NMR technique.

Scientists with USC, Pfizer Worldwide Research and Development and the National Institutes of Health assisted with the research, which was funded by the NIH's National Institute of General Medical Sciences and National Institute of Diabetes and Digestive and Kidney Diseases Intramural Research Program, and the American Cancer Society.


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