Scientific Team Learns Structure of a Key Enzyme : Biochemistry: The three-dimensional model is considered a Rosetta stone to understanding a crucial family of proteins and could lead to the development of cancer-fighting drugs.
A team of San Diego scientists has discovered the three-dimensional structure of a protein found in every human cell, which they believe could lead to customized drugs to battle a range of diseases from cancer to cholera, according to a study released today.
The structure of this particular enzyme is regarded by biochemists as the scientific equivalent of a Rosetta stone for the kinases family of proteins, which play a crucial messenger role in functions as diverse as energy release and memory. Some of the proteins are known to trigger cancers when they malfunction and, armed with knowledge of the structure, scientists hope eventually to create molecular inhibitors that halt that process.
Scientists at UC San Diego and the San Diego Supercomputer Center spent six years uncovering the structure of one particular enzyme, and their findings were published in today’s issue of Science magazine.
“This is the first visual information about the molecule, and it does what looking at something will do--you can infer a lot of functional things from seeing how it unfolds,” said Daniel Knighton, a chemistry graduate student at UCSD and an author of the study. “The lack of information about this has been a real bottleneck in the field.”
In its study, the research team described the structure of an enzyme known as c-AMP (cyclic-adenosine monophosphate) dependent protein kinase.
The protein kinase family, discovered during the past decade, contains more than 200 members. This is the first protein kinase to have its three-dimensional structure solved. Knowing the structure of this one protein kinase gives scientists a prototype for the 200 other related protein kinases that govern a variety of reactions, such as the release of triglycerides in fat cells, which supply energy to the body, or the writing of memory into a neuron in the brain.
“With this information, it opens up a whole new way of approaching how you develop inhibitors,” said Susan Taylor, a UCSD professor of chemistry and an author of the report. “This is the first time you can say, not only can we understand how this particular kinase functions, but how all of them function.”
Protein kinases function like transistors in electrical circuits, serving as an on-off switch for cell growth and governing how cells respond to external stimulus. They are present in all tissues.
Several protein kinases transmit growth signals. When these malfunction, they can contribute to the growth of tumors, which is one reason why they have fascinated scientists, the Science report said.
Experts hope to one day design an inhibitor, which binds to a protein and switches it off, that will stop the tumor-developing process.
“Being able to design specific inhibitors that would target these (cancer-forming) kinases is a goal that has been sought for a long time,” said Taylor, co-director of UCSD’s Computational Center for Macromolecular Structure. “Up until now, there hasn’t been a molecular basis for designing inhibitors.”
For a number of scientists, this discovery may unlock the doorway to developing exciting new drugs.
“This is work that everybody was waiting for, and we are delighted. It’s a very important, elegant piece of work,” said Dr. Edwin Krebs, professor of pharmacology and biochemistry at the University of Washington School of Medicine. Krebs was the leader of a team that isolated this protein kinase in 1968.
Drugs are now developed from compounds that occur in nature, Krebs said. This approach is somewhat random, since scientists must experiment until they find a safe and effective medication, he said.
“We’d like to have drugs that could get into the cell and have an effect,” he said. “And we’d like to think we’ve reached a stage where we can design drugs that can interact with a given protein and affect its function. But to design a drug you have to know the three-dimensional structure of that protein.”
Other scientists cautioned that such work could take years.
“In a long run, this might allow us to generate anti-cancer drugs to inhibit abnormal growth in cancer cells. But that’s certainly a long way off,” said Tony Hunter, a biochemist at the Salk Institute. “Designing something rationally is not so easy.”
Taylor began working in this area 15 years ago. And, six years ago, she teamed up with her colleagues, beginning the research that was published in Science magazine. Chemistry graduate students Daniel R. Knighton and Jianhua Zheng made key breakthroughs in the crystallography that helped the scientists create the three-dimensional model.
Janusz M. Sowadki, a crystallographer with UCSD’s departments of medicine and biology, directed the project.
To create the three-dimensional model, the scientists first crystallized the protein kinase. Then they used X-rays to take a picture of the crystal. Bouncing the X-rays off the atoms in the crystal created a pattern that the team could piece together. But, as Taylor and the others acknowledge, this was the most difficult part of the puzzle.
“This was an incredible experience, we kept getting these little clues,” Taylor said. Referring to the tablet that helped experts decipher ancient Egyptian hieroglyphics, Taylor said, “For us, this is a Rosetta stone.”
C-Amp This newly discovered structure of the c-AMP dependent protein kinase may help scientists decipher the structure of related enzymes. Scientists hope that ultimately it will help them pin down other molecular mechanisms and provide them with targets for drugs to treat a range of diseases and ailments, from cancer to high blood pressure. Source: UCSD & San Diego Supercomputer Center
