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Speeding up drug discovery with rapid 3D mapping of proteins

Christian Klammt, Senyon Choe and Innokentiy Maslennikov

From left: Christian Klammt, Senyon Choe and Innokentiy Maslennikov used their new rapid technique to generate the structure of a hIMP known as TMEM14A, shown here in multiple three-dimensional conformations.

A new method for rapidly solving the threedimensional structures of a special group of proteins, known as integral membrane proteins, may speed drug discovery by providing scientists with precise targets for new therapies. The technique, developed in the lab of Senyon Choe and reported in Nature Methods, provides a shortcut for determining the structure of human integral membrane proteins (hIMPs), molecules found on the surface of cells that serve as the targets for about half of all current drugs.

Knowing the exact three-dimensional shape of hIMPs allows drug developers to understand the precise biochemical mechanisms by which current drugs work and to develop new drugs that target the proteins.

"Our cells contain around 8,000 of these proteins, but structural biologists have known the three-dimensional structure of only 30 hIMPs reported by the entire field over many years," says Choe. "We solved six more in a matter of months using this new technique. The very limited information on the shape of human membrane proteins hampers structure-driven drug design, but our method should help address this by dramatically increasing the library of known hIMP structures."

Integral membrane proteins are attached to the membrane surrounding each cell, serving as gateways for absorbing nutrients, hormones and drugs, removing waste products, and allowing cells to communicate with their environment. Many diseases, including Alzheimer's, heart disease and cancer, have been linked to malfunctioning hIMPs, and many drugs, ranging from aspirin to schizophrenia medications, target these proteins. Choe's team created an outside-the-cell environment, called a cell-free expression system, to synthesize the proteins. They used a Plexiglas® chamber that contained all the biochemical elements necessary to manufacture hIMPs as if they were inside the cell. This system provided the researchers with enough of the proteins to conduct structural analysis.

Prior methods might take up to a year to determine a single protein structure, but using their new method, the Salk scientists determined the structure of six hIMPs within just 18 months. They have already identified 38 more hIMPs that are suitable for analysis with their technique, and expect it will be used to solve the structure for many more.