Scientific Opportunities: Life Sciences
The routine use of synchrotron radiation for single crystal diffraction studies has revolutionized macromolecular structural biology. With the availability of brighter X-ray sources, the size and complexity of macromolecules that can be studied has increased by an order of magnitude, or three orders of magnitude in mass (see figure). However, crystals of the most complex structures that are suitable for diffraction are often scarce and difficult to obtain. Therefore, continuing advances in synchrotron radiation sources, detectors, and software are required to tackle the most challenging problems, which are the ones most likely to make a significant impact on our knowledge of the functioning of living systems.
The growing use of synchrotron sources for macromolecular crystallography has increased the pressure on existing facilities to upgrade existing, or construct new, sources and beamlines. This problem is particularly acute in the Northeastern United States, where aging synchrotron sources at Brookhaven National Laboratory and Cornell University find it increasingly difficult to meet the experimental demands of a large group of crystallographers working in this region.
Biological and biomedical research has entered a new era, with an increasing emphasis on understanding the functional and physical connections between macromolecules - how the molecular components of cells and tissues are connected in biochemical pathways, cellular responses, and functioning organs. This requires first determining the structures of these components, and the field of structural biology is now poised to make invaluable contributions to our understanding of assemblies of interacting macromolecules.
NSLS-II is needed to meet the needs of scientists who will accomplish this difficult work.
Large Molecular Assemblies
Other large assemblies comprised of proteins and nucleic acids are continuously being identified and will be the target of high-resolution crystallographic studies in the future. A high brilliance X-ray source will be essential to make progress with these challenging projects.
The work on the voltage-dependent potassium channel (see figure), just awarded the 2003 Nobel Prize in Chemistry to NSLS user Roderick MacKinnon, is an example of the dramatic impact that structural studies of membrane proteins have in the understanding of cellular function. Voltage-dependent cation channels open and allow ion conduction in response to changes in cell membrane voltage, controlling electrical activity in nerves and muscle.
Local access to an extremely bright source of X-rays was critical to the success of MacKinnon's work, and future work in this area depends strongly on frequent access to a bright X-ray source to provide the constant feedback between the synchrotron and the biochemistry lab that is essential.
The Protein Structure Initiative, a structural genomics program funded by the National Institutes of Health - National Institute of General Medical Sciences (NIH-NIGMS), aims to provide structural information for all proteins in all naturally occurring protein sequences using a combination of experiment and comparative protein structure modeling. NSLS-II will play a major role during and after the production phase of the Protein-Structure Initiative. NSLS-II undulator beam lines dedicated to structural biology can be used to handle this load: crystals will be screened for quality; if quality is adequate, sufficient data to solve the structure will be measured and all results recorded in an experiment-tracking database.
Today virtually every large pharmaceutical company has a crystallography group. Recognizing the need for rapid and frequent access to synchrotron radiation, twelve of these companies operate their own beamline at the Advanced Photon Source at Argonne National Laboratory.
A critical challenge faced by pharmaceutical crystallographers is that the macromolecules studied are very often human proteins, since the aim is to treat human diseases. Human proteins can be very difficult to work with, and growing crystals large enough to study can be daunting. Another challenge is time. After the first structure is determined, there are several more steps to take before one can determine the properties that might be required of a drug. Synchrotron-based crystallography, performed at convenient, efficient synchrotron facilities like NSLS-II, helps to optimize crystallization methods and solve new structures easily.
Last Modified: April 2, 2013