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Less Fat Makes Better Process For Designing New Drugs

08.12.2004


Biochemists at Ohio State University and their colleagues have overcome one of the major obstacles to drug design, by trimming some of the fat from a molecular sponge that scientists use to study proteins.

In the December issue of the journal Structure, the biochemists report using their method successfully in experiments with two common cellular proteins. The results suggest that scientists could one day use the method as a step in designing drugs for diseases such as cystic fibrosis, Alzheimer’s, and tuberculosis.

Proteins are part of the cell membranes of living organisms, and they are the gatekeepers that regulate what enters and leaves a cell, explained Martin Caffrey, professor of chemistry at Ohio State. To design a drug that will target a particular protein, scientists need to view the protein’s structure in detail, and that involves removing the protein from the cell membrane and forming it into a crystal that can be viewed using x-rays.



It’s not easy to form a pliable protein into a rigid crystal, and scientists are working to develop reliable tools to do the job. “Crystallizing proteins is considered an art. We want to turn it into a science,” Caffrey said. One promising tool is a slab of intertwined lipid and water molecules -- a kind of wet, fatty sponge that soaks up thousands of proteins at once and draws them together into crystals.

The sponge is full of watery pores that offer surface area for chemical reactions. One gram of the stuff has more surface area than a football field. The sponge method, called “cubic phase,” or “in meso,” crystallization, has been around since the 1990s. But because most proteins are difficult to crystallize, scientists have only been able to study a handful of proteins this way.

In Structure, Caffrey and his coauthors describe how they improved upon the method. They built a sponge out of smaller fat molecules than are normally used, creating larger pores and thinner membranes inside the sponge that gave the proteins more room, so they were more likely to bind together. In tests, the biochemists were able to form crystals of two common proteins, bacteriorhodopsin (bR) and BtuB, which is a carrier for vitamin B12.

The bR protein had been crystallized with the traditional “in meso” method before, and so it was a good benchmark for the test. But to the biochemists’ knowledge, this is the first time that a protein such as BtuB has been crystallized with the “in meso” method. They were able to crystallize BtuB using both the traditional, thicker sponge and the new, thinner sponge.

BtuB belongs to a class of proteins called beta-barrel proteins, which are made of sheets of protein rolled up into a cylinder. This particular shape of protein has defied crystallization with a molecular sponge before. Yet BtuB is of particular interest to scientists, because it is found in the outer cellular membrane of E. coli, a bacterium often used in laboratory research. “We were able to get the BtuB to crystallize with the traditional method, but it worked even better with the new method,” Caffrey said.

Right now, there are thousands of other important proteins that scientists can’t crystallize, Caffrey said. His modified sponge may work for some of them, too. The BtuB crystals made with the less fatty sponge were twice as large as BtuB crystals made with the thicker sponge -- 200 micrometers across, compared to 100 micrometers (about the width of a human hair). Larger crystals are easier to manipulate in the laboratory, Caffrey said, and they can be viewed with less expensive equipment than is required to view smaller crystals.

He and his colleagues will have to develop the method further before it can be used with a wide variety of proteins. For instance, some proteins may only crystallize at high or low temperatures. The current experiment worked at room temperature (20 degrees Celsius, or 68 degrees Fahrenheit) but not at temperatures closer to body temperature (40 degrees Celsius, or 104 degrees Fahrenheit).

The heat caused the fat molecules to kink up, which stifled the crystallization, Caffrey said. He suspects that scientists may be able to tailor the size of the fat molecules further to suit different proteins at different temperatures in the future.

Understanding protein structure is an important first step in designing protein-specific drugs. Should the new crystallization method prove versatile, it could help scientists develop new treatments for a wide variety of diseases, including Alzheimer’s, Parkinson’s, diabetes, cataracts, cystic fibrosis, and tuberculosis.

Caffrey’s Ohio State collaborators were David Hart, a professor of chemistry; Lisa Misquitta, and undergraduate student in biology; Yohann Misquitta, a doctoral student in biophysics; Vadim Cherezov, a research associate; Jakkam Mohan, a postdoctoral researcher; and Orla Slattery, a visiting scholar from the University of Limerick in Ireland. Other coauthors on the paper included William Cramer and Mariya Zhalnina, both of Purdue University.

The National Institutes of Health, the National Science Foundation, and Science Foundation Ireland funded this study.

Martin Caffrey | EurekAlert!
Further information:
http://www.osu.edu

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