What happens in a lab that incorporates chemistry, biology, physics, particle accelerators, proteins, computers and 3-D glasses? Using various methods and equipment, Cornell researchers have determined new protein structures that could be useful in understanding and developing drugs to combat cancer.
Yan Zhang grad and Prof. Steven Ealick, chemistry and chemical biology, have figured out the structure of AIRs kinase, an enzyme involved in purine nucleoside biosynthetic pathways. The two researchers were able to compare the structure of this particular protein to eight other kinase proteins with similar structures. They noticed that only some of the enzymes in this group of kinases have a lid over the active site, where substrates bind. Ealick said that he believes that the lid over the active site evolved because this allows the enzyme to work more efficiently.
Determining protein structure is a complex process. First, a good protein crystal must be obtained. Then the crystal is irradiated with an x-ray beam. This can be done in the lab or using the particle accelerator at the Cornell High Energy Synchrotron Source or the Northeastern Collaborative Access Team beamline at the Advanced Photon Source at Argonne National Laboratory in Chicago. Next the optical transform, an x-ray diffraction pattern, is taken multiple times from different angles. They are then converted into an image of a molecule using computer programs. The researchers can then look at the structures through 3-D glasses.
Zhang produced the protein structure of AIRs kinase in a little over two months. Ealick said that about 25 years ago, it would take five to six years to work out one protein structure, while now, it takes on average five weeks due to better methods and equipment.
“Working out 3-D structures of proteins is important for determining enzyme mechanisms, in terms of drug design — how to activate a particular protein, and protein evolution — finding patterns between structures,” Ealick said.
For drug design, knowing protein structures could also be beneficial in finding out how anti-cancer or antiviral drugs work and how to design drugs that will work. Future research might allow scientists to genetically engineer proteins as synthetic tools or catalysts for chemists. “If you know the mechanism, or how it works, you can change it to make it do what you want,” said Zhang. She explained that this could be useful in anti-cancer gene therapy where delivery of a special enzyme is followed by the treatment of a non-toxic pro-drug that is activated in a specific area.
Archived article by Vanessa Hoffman
Sun Staff Writer