July 1, 2005  


Bacteria Protein Structure Discovered

By Monica Bobra

Using SSRL, three scientists from the Salk Institute for Biological Studies have discovered the three-dimensional structure of a protein that bacteria use to make anti-cancer, anti-viral, anti-inflammatory and anti-oxidant compounds. By effectively engineering this protein, scientists may be able to create new drugs with therapeutic properties. The Salk Institute scientists reported their results in the June 16 issue of Nature.

A schematic diagram of the Orf2 protein allows scientists to visualize it in three-dimensional space. The helical structure is known as a PT barrel. Thin strands of molecules reside within the PT barrel; the sphere in the protein's core represents magnesium.
(Image courtesy of Interactions.org)

The bacterial protein, known as Orf2, contains a previously unknown structure shaped like a barrel. Scientists discovered this structure using a process called x-ray crystallography, a technique in which x-rays, produced by synchrotron radiation, hit the protein’s atoms and diffract to produce a two-dimensional pattern. Computers then interpret a set of such patterns and construct a high-resolution three-dimensional image. Researchers gathered data at SSRL, the National Synchrotron Light Source (NSLS) at BNL and the European Synchrotron Radiation Facility.

“Looking at the protein’s structure is like opening up a clock and understanding how all the parts fit together and work in unison,” said co-author Joseph Noel. “With x-ray instruments from our lab at the Salk Institute, we looked at Orf2 from 30 feet away. With SSRL, we can look at it with a magnifying glass if we need to. That’s an essential part of the whole process.”

Orf2 is one of a small number in a recently isolated family of proteins that create compounds with anti-microbial, anti-cancer, anti-viral, anti-inflammatory and anti-oxidant properties. It accomplishes this remarkable task by adding hydrocarbons known as prenyl groups to flat benzene-like molecules. By manipulating Orf2 using knowledge of its three dimensional shape, scientists could engineer therapeutic drugs.

“When we first looked at it, very quickly, we thought: this is one of the most common 3-D folds known in nature,” said Noel, referring to a common helical protein structure known as a TIM barrel. Soon after, the team realized Orf2’s shape was incredibly distinctive; its amino acids, which form the protein’s building blocks, are arranged in an entirely different manner.

“We currently use the protein as a surrogate chemist, allowing it to catalyze chemical reactions that would be difficult or impossible to do with traditional chemistry,” said Noel. In this way, the researchers slightly modify existing chemicals, which may lead them to discover new drugs. “We hope to use and engineer the protein to create novel compounds,” said Stéphane Richard, who helped make the discovery.

In addition, studying Orf2’s structure allows the scientists to understand the fundamental process of molecular evolution. The team is analyzing the amino acid sequence of closely related proteins to understand how Orf2 has changed over time. “Using laboratory techniques for genetic manipulation,” said Noel, “we can now make changes to Orf2 and its relatives in a manner resembling the path that evolution has taken over the last half a billion years or so.”


The Stanford Linear Accelerator Center is managed by Stanford University for the US Department of Energy

Last update Friday July 01, 2005 by Topher White