Membrane Protein Structure Visualized Using Emerging X-Ray Technology despite Existing Damage

Australian researchers have found a way to measure the structure of membrane proteins in spite of being damaged when using X-ray free-electron lasers (XFELs), a discovery that will help fast track the development of targeted drugs using new XFELs technology.

Approximately 70% of drugs on the market today depend on the activity of membrane proteins, which are complex molecules that form the membranes of the cells in our body. A major problem for the design of new pharmaceuticals, often known as the "membrane protein problem,” is that they do not form the crystals needed to enable further investigation of the structure to design better drugs.

A large international effort is being undertaken to determine the structures of membrane proteins using XFELs--large facilities that create such a bright beam of X-rays it is possible to see the X-ray light bouncing off a single molecule without forming a crystal.

Prof. Keith Nugent, and ARC Federation fellow and director of the Australian Research Council Center of Excellence for Coherent X-ray Science (CXS) at the University of Melbourne (Australia) reported that a key problem was that the light from an XFEL was so bright a molecule would start to disintegrate in less than one thousandth of a millionth of a millionth of a second.

In an article published online December 19, 2010, in the journal Nature Physics, Prof. Nugent and Associate Prof. Harry Quiney from the ARC Center of Excellence for Coherent X-ray Science (CXS) have developed a method by which the damage from the XFEL pulse may be included in the data analysis. Associate Prof. Quiney, also from the School of Physics at the University of Melbourne, reported that the study's findings revealed that high-resolution molecular structures may be obtained from X-ray scattering data using a few-femtosecond pulse from an XFEL, even if the interaction resulted in significant electronic damage to the target. "This result has far-reaching implications for the future development of structural biology, because it removes a significant obstacle to the practical realization of the molecular microscope using XFEL sources,” he said.

The technology also provides significant clues into the complex, raging, and little-understood interactions that are driven by the interaction of an XFEL pulse with an atom, molecule, or solid. The scientists' approach uses advanced molecular physics and precise data analysis to determine a new approach to measuring molecular structure. Although still at the theoretic and computation level when put into practice, this finding should remove a major hurdle in the path to solving the membrane protein problem.

In 2010, CXS signed an agreement with Japanese colleagues and will host the 4th Asia-Oceania Workshop on Science with X-ray Free Electron Lasers in 2011.

Prof. Nugent noted that this was an extremely exciting time for X-ray science. "My colleagues and I are convinced that our recent work is a critically important step forward,” he said. "We are very much looking forward to working with our Japanese colleagues in the coming years.”

The first XFEL began operating at Stanford University in Palo Alto, CA, USA, in 2009 and the second, the SPring8 facility in Harima Science Park City, Hyogo Prefecture, Japan, will start in 2011. A third is under construction in Europe to commence in 2014.

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