Protein Structures: A Key to Unknown Treasures

It took Dr. Max Perutz 22 years to determine the structure of hemoglobin, for which he was awarded the Nobel Prize in 1962. Today, thanks to extraordinary technological advances, including advances in x-ray crystallography techniques initially developed by Dr. Perutz, some protein structures can now be determined in a matter of hours. And, as we are learning, this research is becoming an essential component of developing new cancer treatments.

Yesterday, at the U.S. Department of Energy's (DOE) Argonne National Laboratory outside of Chicago, a ceremony was held to dedicate the first of three new macromolecular crystallography beamlines at Argonne's Advanced Photon Source (APS) synchrotron. This synchrotron produces the most powerful radiation in the Western Hemisphere. The National Cancer Institute (NCI) teamed with the National Institute of General Medical Sciences (NIGMS) and DOE to fund the beamlines' construction and took a lead role in facilitating the construction process. As part of our partnership with NIGMS, NCI receives dedicated time on the beamlines for its researchers.

The synchrotron, one of only a handful in the United States, is a powerful tool for deciphering the structure of proteins involved in cancer and other diseases that affect hundreds of millions of people around the world. The new experimental facility includes several novel design features, including the ability to split a single beamline into two without sacrificing intensity - effectively doubling its work capacity.

Although we have become increasingly adept at identifying cancer-related genes and the proteins they produce, there is still much to be learned about cellular mechanisms, the effects of mutant proteins on these mechanisms, and how to design agents that can effectively disrupt these proteins' aberrant behavior. That is why NCI, with funds from the Division of Cancer Biology, has partnered with NIGMS to develop the new beamlines. By advancing efforts to elucidate protein structures, we believe we can bridge that knowledge gap.

Structural biology research has already helped generate important advances in our understanding of transcription, translation, DNA repair, cell death (apoptosis), and protein degradation mechanisms. It also is beginning to play an important role in drug development, as was the case with the development of two agents that have demonstrated the ability to overcome resistance to the targeted agent imatinib (Gleevec). Only after researchers solved the structure of imatinib bound to BCR-ABL could agents be developed that bind to the mutated forms of BCR-ABL to which imatinib can no longer bind.

Progress in this area has been exponential. NIGMS' Protein Structure Initiative has given rise to important technological advancements and generated the structures of 1,000 (primarily bacterial) proteins. And last month, an Anglo-Canadian effort, the Structural Genomics Consortium, reported that, in less than 1 year, it had determined the structures of 50 complex proteins relevant to human diseases, including cancer.

We're glad to be part of such an exciting effort that will help untangle mysteries scientists have pondered for many years. We believe that this research will generate many important advances that move us closer to the 2015 goal.