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September 24, 2001

Rhodopsin Research May Led to New Field of Drug Discovery

In a study that may open an entirely new field of drug discovery to the pharmaceutical industry, a UConn research team has unveiled a complete three-dimensional structure of rhodopsin, a protein fundamentally responsible for vision, and a member of a large family of cell membrane proteins that turn on and off cells in response to biological signals.

The study, just released by the journal Biochemistry on its website, uses a novel method for scientists to discover the elusive molecular architecture of other such signaling proteins, called G-protein coupled receptors (GPCRs) that regulate a wide variety of cellular activity. The article will be published in print later this fall.

"This research provides the first detailed structural information on how any GPCR propagates its signals and a potential alternate paradigm for securing three-dimensional structural information on other membrane receptors," says Philip L. Yeagle, professor and head of molecular and cell biology and co-leader of the research team, together with Arlene Albert, also a professor of molecular and cell biology. The team includes two post-docs, three graduate students and three undergraduates.

"Knowing structure is a tremendous benefit in order to find the target you want to go after; it gives you a place to go," says Yeagle.

"GPCRs are the surface targets on cells to which drugs bind and activate or deactivate biological signals. They therefore have been critically important targets for medications that treat conditions regulated by GPCRs. More than 60 percent of all prescription drugs on the market today, including 12 of the top 20 selling drugs, directly or indirectly, target GPCRs, accounting for over $200 billion of the pharmaceutical industry's annual sales worldwide.

However the potential for GPCR-based drugs remains largely untapped, since less than 10 percent have been identified. It is now estimated by the Human Genome Project that nearly 2,000 so-called "orphan" GPCRs -- whose function is unknown -- may exist in humans, and most major pharmaceutical companies today have active GPCR drug discovery programs.

What makes determining the structure of such important membrane proteins a huge unsolved question is that the usual methods for structure determination are largely ineffective, explains Yeagle. That is why only one GPCR structure has been solved.

Rhodopsin, the receptor for light in the eye and widely regarded as the archetype of G-protein coupled receptors, is one of the most extensively studied of cell membrane proteins, because it is responsible for some kinds of blindness, says Yeagle. Earlier research had shown information about the core of the protein, but until now nothing was known about the surface that actually communicates the signals.

The idea occurred to Yeagle and Albert that perhaps an alternative way to obtain the needed structural information for proteins like rhodopsin was to "divide and conquer", utilizing smaller segments of the protein like Lego pieces whose structure could be readily determined, and reassembling them into a structure of the whole as a child would build a toy from Legos.

They chose to test this idea on a protein whose three-dimensional structure was already known. As described in the August edition of Biophysical Journal, they disassembled the membrane protein bacteriorhodopsin into a set of pieces whose structure they then determined individually. Almost all the pieces faithfully reported the proper structure from the corresponding part of the whole protein. Using clues from other experiments (but not from the known structure) they then reassembled the pieces into a structure of the whole protein which agreed well with the known structure. The test of the method was a success.

Yeagle and Albert then applied this method to the structure of rhodopsin. The result was a complete three-dimensional structure. This structure revealed structural details in excellent agreement with the known biochemistry of this receptor, and provided critical new information on how this signaling machine talks to the cell.

"It's a somewhat heretical technique," says Yeagle, "but in effect we have a method that gets us around roadblocks. These new results suggest that our technique can be applied to other signaling proteins and accelerate drug targeting efforts."

David Bauman

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