After seven years of work, researchers have succeeded in deducing the three-dimensional structure of an elusive and complex protein enzyme that is central to regulating the body’s largest family of receptors. These receptors, called G-protein-coupled receptors, nestle in the cell membrane and respond to external chemical signals such as hormones and neurotransmitters, to switch on cell machinery.
The thousands of such receptors throughout the body play a fundamental role in the mechanisms of sight, smell and taste, and in regulating heart rate, blood pressure and glucose metabolism. The receptors are by far the most common target for drugs that affect cardiac output, blood pressure and many other physiological functions. Thus, said the researchers, their fundamental discovery could guide pharmaceutical companies in creating a new class of drugs that aim not at blocking the receptors themselves, but at modulating the machinery that regulates them. Such drugs could treat a range of disorders from congestive heart failure to Parkinson’s disease, they said.
The newly revealed structure of this receptor "off-switch" -- called a G protein-coupled receptor kinase (GRK) -- reveals the protein as the molecular equivalent of a three-armed octopus, with independent segments capable of performing multiple regulatory functions at once. Kinases are enzymes that act as molecular switches by adding phosphates to other proteins.
To reveal how GRK2 interacts with the G protein, the researchers obtained the structure of GRK2 attached to a subunit of the G protein to which it normally binds, or complexes. Lefkowitz noted that a particularly striking achievement was the production of pure crystals of the highly complicated protein complex by Tesmer and his colleagues.
"The results of this prodigious effort were some really striking and unanticipated insights into the structure of the GRK2 complex," said Lefkowitz. "For one thing, the three domains are not aligned in a straight line, but assembled as if they were the three vertices of an equilateral triangle. And their spacing allows them to perform their docking and catalytic functions simultaneously.
"This means that GRK2 could be a remarkably effective and multitasking mechanism for turning off G protein signaling." Thus, he said, the GRK2 is built to bind to the receptor and phosphorylate it, allowing attachment by beta arrestin, and at the same time, bind the G protein to switch it off.
"This structural determination has significance at two levels," concluded Lefkowitz. "First, it gives us important new information about the basic biology of this important regulatory mechanism. And second, it gives us the detailed molecular coordinates of this structure that guide drug developers in designing specific compounds to regulate the enzyme."
Contact: Dennis Meredith, email@example.com
Dennis Meredith | EurekAlert!
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