Brain receptor's intricate structure revealed by Oregon scientists
December 2nd 2009 21:20
By Joe Rojas-Burke, The Oregonian
Eric GouauxA tangle of protein strands coil and fold together to form the the glutamate receptor, a molecular machine that relays signals between brain cells. Researchers at Oregon Health & Science University solved the mystery of its structure.
This week, scientists Eric Gouaux, Alexander Sobolevsky and Michael Rosconi at Oregon Health & Science University published the first complete structure of a brain cell glutamate receptor. The tangle of protein strands coil and loop together to form a complex but symmetrical molecular machine. It controls the flow of ions into cells that drives electrical pulses down nerves.
Malfunctioning glutamate receptors play a role in Alzheimer's disease, epilepsy, schizophrenia, and many other diseases. Knowing the full structure could help researchers find new treatments.
"I am not sure whether non-crystallographers can truly appreciate what an astonishing tour-de-force this is, what a huge amount of work lies behind the elucidation of such a complex structure," says Radu Aricescu, a scientist at the University of Oxford who was not part of OHSU the team. Crystallography is the science of mapping the arrangement of atoms in large molecules such as proteins.
Gouaux and colleagues pursued the structure for six years before starting to make headway. "Then we worked like crazy men for about five years," he says. The result of team's 11 years of labor appears in the journal Nature and they have deposited all of the structural data in the online, freely accessible Protein Data Bank. The National Institutes of Health and the Howard Hughes Medical Institute funded the research.
Charting the receptor's structure "revealed a completely unexpected mechanism of assembly," says Mark Mayer, a scientist at the NIH Laboratory of Cellular and Molecular Neurophysiology in Bethesda, Md. That insight is forcing neuroscientists to rethink prevailing ideas about how glutamate receptors work.
The glutamate receptors are a complex family of receptors with diverse roles in the brain. The OHSU team focused on AMPA receptors, one of the three major subtypes.
While other scientists had previously mapped large parts of the structure, the OHSU team is the first to put it all together, "and bring into clarity decades of work performed by other groups," Mayer notes.
"It will open up new avenues for structure-based drug discovery that could shave off years and millions of dollars in comparison to the traditional trial-and-error drug development process," says Rongsheng Jin, an assistant professor at the Burnham Institute for Medical Research in La Jolla, Calif.
But much work remains. Aricescu points out that the reported structure represents a frozen "snapshot" of the receptor in a closed position, when in living cells it is a dynamic, shape-changing machine. The challenge now, he says, is to figure out the structural conformation at higher resolutions and when it is open or in conformations stabilized by drug compounds known to bind with the receptors.
"Such structures may contribute to rational drug design, but this is still a remote target," he says.
-- Joe Rojas-Burke
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