This renewal grant application seeks funding for a project that uses organic compounds that bind two proteins simultaneously in order to activate cellular processes including protein translocation, signal transduction, and gene transcription. Activation results from the increased effective molarity of a target protein in the vicinity of another protein, usually one having an enzymatic activity (for example, a kinase, polymerase, protease). Transferal of information by altering the effective molarity of proteins, often through adapter proteins, is becoming recognized as a fundamental principle in biology, rivaling the allosteric mechanism. The """"""""dimerizer"""""""" project was initiated four years ago, when their principle was not generally recognized and certainly not widely accepted. Our premise was that if effective molarity was the key to controlling cellular processes, we could control these processes by synthesizing cell permeable, """"""""small molecules"""""""" that increase the effective molarity of, for example, protein substrates of enzymes. The now widespread acceptance of the role of effective molarity in biology is due in part of the success of the dimerizer project. The project has also provided the first general approach to controlling protein function by activation in cells, tissues, and animals. Understanding a protein's function often requires altering its function. This has been most frequently accomplished by genetic manipulation, i.e. mutation the gene encoding a protein of interest. Alternatively, it is possible to alter protein function directly, using small molecules that bind to the target protein (chemical genetic approach). Inactivation (equivalent to a """"""""loss of function"""""""") to become a common outcome. The planned research is expected to play a vital role in extending the chemical genetic approach by using small molecule dimerizers to understand and control the cellular, development, and physiological function of several target proteins and pathways. The planned research is aimed at making optimal reagents available to the scientific community and at illustrating their use in the context of several vexing problems in biology, including the mechanism of signaling through the insulin receptor and the ability to control that signaling with small molecules.
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