02/14/2012 0 Comments Contact Our News Editors

A team of scientists from The Scripps Research Institute, collaborating with members of the drug discovery company Receptos, created the first high-resolution virtual image of cellular structures known as S1P1 receptors, which are critical in controlling the onset and progression of multiple sclerosis and other diseases.

Scientists at Scripps Research and Receptos have created the first high-resolution virtual image of cellular structures called S1P1 receptors, which are critical in controlling the onset and progression of multiple sclerosis and other diseases. Image Source: The Scripps Research Institute
The molecular map is pointing researchers toward promising new paths for drug discovery and aiding them in a better understanding of how certain existing drugs work.

The molecular structure is the first-ever-to-be-determined lipid G protein-coupled receptor (GPCR). “There’s something special about the S1P1 receptor,” says Hugh Rosen, MD, PhD, a Scripps Research chemical biologist who co-led the work with Raymond Stevens, PhD, a structural biologist also from The Scripps Research Institute. “The biological consequences of even small changes with this receptor are profound. Understanding its structure provides clues about fundamental processes important in both health and disease.”

“Being able to finally look at a lipid GPCR and the occluded cell surface binding pocket was a surprise but explains many of the issues we wondered about,” says Stevens. “It is likely that other members of this subfamily will have a similar protein architecture.”

The study is a result of research to develop methods to determine the structure of GPCRs, the receptor biology and chemical tools to stabilize such molecules, and a multi-disciplinary collaboration between the two labs.

The work reveals the structure of the S1P1 receptor, a protein embedded in the membranes of various cell types. When natural ligands (such as the signaling lipid sphingosine 1-phosphate or potential drugs) make specific interactions deep in the receptor, portions of the receptor change shape to trigger cascades of chemical reactions inside the cell important to the maintenance of health.

Researchers have long known that S1P1 receptors play critical roles in controlling multiple sclerosis and other diseases. One way the receptors do this is by regulating the flow of certain white blood cells, or lymphocytes, out of lymph nodes.

This is critical because in patients with multiple sclerosis, auto-reactive lymphocytes attack the protective sheaths of nerve cells in the brain, causing malfunctions in the way the central nervous system transmits signals through the body. The S1P1 receptors are also involved in the progressions of harmful scarring and swelling in response to lymphocyte damages in the brain.

Gilenya, the first oral drug approved to treat multiple sclerosis, reduces this lymphocyte flow out of the lymph nodes in ways identified by Rosen’s laboratory. Based on a screening lead from the National Institutes of Health Molecular Libraries Small Molecule Repository, Rosen and Scripps Research Chemistry Professor Ed Roberts discovered and optimized other modulators of S1P1 receptors. This led to RPC-1063, a compound in clinical trials for multiple sclerosis by Receptos, a company co-founded by Rosen and Stevens.

Rosen’s lab has also shown that modulating S1P1 receptors can protect mice from a pandemic flu virus that shows that the receptors may also be good drug development targets for other conditions tied to immune responses.

The new study used the technique of x-ray crystallography to reveal the high-resolution 3D image of the S1P1 receptor. The results provide scientists with new details about the receptor’s mechanism of action.

One aspect of the receptor structure that is of particular interest is the binding pocket for the natural ligand or potential drugs that activate the receptor responses. The structure revealed how the binding pocket shifts to activate signaling. Understanding how that occurs makes it easier to identify additional compounds that might have effects in controlling the receptors.

With the structural information in hand, the scientists can advance efforts to understand the specific chemical transformations that drive the cellular responses tied to multiple sclerosis and other diseases. “Better understanding always allows you to think about applications in a variety of ways that you might not have thought about before,” says Rosen. “This is an area that will keep us busy for many years to come.”

The S1P1 receptor structure has already yielded benefits, says Michael Hanson, a scientist and director at Receptos. “The structure has helped us understand the details regarding receptor-ligand interactions for this receptor and structural data can be used more routinely for drug discovery projects of other GPCRs.”

The research was in Science.