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Scripps Research team discovers new details about medically important protein family
Date:3/10/2011

eptor, a member of the GPCR family sometimes referred to as the "caffeine receptor," bound to a full agonist. The team discovered that when the receptor bound to this particular agonist, it took on a new shape, as expected, but it then remained in that new conformation, rather than continuing to move.

"We were surprised to discover a super stabilizing agonist," said Stevens. "While dynamics is certainly a critical component of receptor signaling, it is not as extreme or the complete story as previously thought. The agonist we solved with the A2A structure highlights the fact that certain agonists can stabilize the receptor in a single conformation without the presence of an intracellular binding partner such as a G-protein. This is also teaching us that what we learn from one receptor or one agonist/antagonist interaction should not necessarily be a rule for all GPCRs at this early stage of GPCR structure discovery. We need to study multiple systems in-depth before we will really understand this receptor family."

The finding has important implications for drug design. In some diseases, such as Parkinson's disease, potential treatments involve blocking the functions of certain GPCRs using antagonists. But for treating other diseases such as COPD, researchers are trying to develop agonists that activate GPCRs. This new finding could facilitate the design of such agonist-based drugs.

Ward Smith, director of the National Institutes of Health (NIH) Protein Structure Initiative (PSI), which funded the study, said, "Determining the structure of the active form of the A2A adenosine receptor represents just the kind of significant accomplishment that the Protein Structure Initiative was intended to foster. Now that we know what the active form looks like, we have a much better idea of how this important class of cellular gatekeepers functions and how we might manipulate their activity in treating disease."

Decades-Long Vision Yields R
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Contact: Mika Ono
mikaono@scripps.edu
858-784-2052
Scripps Research Institute
Source:Eurekalert

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