Molecular Structure of Cancer-Related Proteins Identified

NEW YORK, December 18, 2001 - Research published in this week's issue of Nature describes the molecular structure of two cancer-related proteins binding to one another. Scientists identified the biochemical and signaling properties of these molecules using a process called X-ray crystallography. The technique yielded the first-ever detailed pictures of the proteins interacting with each other, indicating which areas are most essential for the development of cancer.

The characterization of the structure may eventually be used to design novel drugs that interfere with the normal function of these proteins and prevent cancer growth. The work is the result of a scientific collaboration led by Memorial Sloan-Kettering Cancer Center.

Tyrosine kinases are key enzymes responsible for communication between receptors on the cell's surface and pathways within the cell. Researchers determined the structure of an Eph receptor tyrosine kinase bound to its corresponding ligand molecule called ephrin. Interactions between Eph receptors and their specific ephrins lead to an array of cellular processes, including those that regulate cell proliferation, survival, adhesion, and movement. They are especially important in angiogenesis - the development of new blood vessels essential for the progression of cancer.

According to the authors, the structural detail of the complex provides a framework for the development of potential drugs that could block Eph signaling. "Given the importance of Eph receptor kinases and ephrins in cardiovascular function, nerve regeneration, and cancer, the results could be the first step towards the future development of novel therapeutic strategies," said Dimitar Nikolov, PhD, head of the Structural Biology and Neuroscience Laboratory at Memorial Sloan-Kettering Cancer Center, and senior author of the study.

The research team cloned the Eph and ephrin mouse genes, expressed the corresponding proteins in bacteria, and then purified them into miniscule crystals that diffract when bombarded with high energy X-rays. Researchers recorded the diffraction spots on a sophisticated camera and used a powerful computer to analyze the way in which the atoms scattered the X-rays. The resulting data were used to produce a three-dimensional picture of the proteins.

The X-ray crystallography of the proteins was conducted at the National Synchrotron Light Source (NSLS) at the US Department of Energy's Brookhaven National Laboratory and at the Cornell University High Energy Synchrotron Source (CHESS). The light sources generate powerful X-rays, key to capturing the first detailed images of the proteins.

"The sample is continuously rotated to get a series of diffraction patterns. Mathematical analysis of these patterns provided details that help explain the development of cancer," said Brookhaven crystallographer and study co-author Kanagalaghatta Rajashankar.

The image clearly shows a channel in a specific surface area of the receptor. The channel has a high affinity towards the ligand, which contains a loop that penetrates deep into the channel causing slight structural changes and initiating processes that determine the fate of the cells, including the formation of blood vessels.

"Our results may be used to discover and develop small molecules resembling the natural ligand, competing with the binding process and ultimately preventing the growth of cancer," said Juha-Pekka Himanen, PhD, research associate at Memorial Sloan-Kettering and lead author of the paper.

Scientists from the University of Texas Southwestern Medical Center at Dallas, and the Royal Melbourne Hospital in Australia also contributed to the research.

Memorial Sloan-Kettering Cancer Center is the world's oldest and largest institution devoted to prevention, patient care, research, and education in cancer. Our scientists and clinicians generate innovative approaches to better understand, diagnose, and treat cancer. Our specialists are leaders in biomedical research and in translating the latest research to advance the standard of cancer care worldwide.