Kinase molecules are active in nearly all signaling within and between cells, and are required for everything from cell division and development to learning and memory. Genetic approaches that inhibit one kinase usually induce compensatory responses such as over-expression of related kinases. Efforts to get around this problem have led to other roadblocks. Overall, the genetic approach has not been so successful in studying kinases without disrupting overall cell function, Shokat said.
The new research succeeds precisely in this arena. The chemicals inhibit just the catalytic effect of the specific kinase under study and do not alter its other functions. More importantly, the function of other kinsases remains unaffected, keeping the cell functioning and allowing experiments to determine the specific function of the kinase.
In experiments with yeast -- done in collaboration with another UCSF scientist, David Morgan -- the resultant "mutant kinase" was able to perform its normal function in the organism but was clearly distinguishable from all other kinases, establishing that the technique is a potent new research tool.
The research success demonstrates for the first time that a precise knowledge of the composition and structure of kinases and their chemical inhibitors can be used to design new kinase/inhibitor pairs by combining the tools of organic chemistry and protein engineering. This offers a powerful alternative to using genetic mutations to study proteins and determine their biological roles.
The researchers demonstrated the successful technique on five large families of kinases. The broad-ranging success is expected to allow scientists for the first time to isolate the function of hundreds of kinases. The research demonstrates the power of combining genetic and chemical approaches.
The research goal, Shokat said, has been to find a chemically-based
approach to study all kinases
Contact: Wallace Ravven
University of California - San Francisco