Drug May Arrange Therapeutic Unions

"Marriage Broker" Drug May Arrange Therapeutic Unions
Release Date:
Doris Brody, NIGMS

In studies that will greatly aid researchers who are seeking to develop a control system for gene therapy, NIGMS grantee Stuart Schreiber, Ph.D., and his colleagues at Harvard University in Cambridge, MA, have determined the structure of a complex consisting of the immunosuppressant drug rapamycin bound to two proteins, called FKBP12 and FRAP. Without rapamycin, FKBP12 and FRAP would not normally link up. The structure studies show how the shape of rapamycin permits it to bring these two proteins together. Drugs such as rapamycin are particularly attractive candidates for linking (and thus controlling) parts of "genetic switches" because they are relatively small molecules that slip easily into cells.

The determination of the structure of the protein-rapamycin complex is the latest step in a long series of studies that began with Dr. Schreiber's work on cell signaling pathways (the means by which messages from the outside are relayed through the cell to the nucleus, where specific genes respond). For years, Dr. Schreiber, a chemist, worked to define some of the fundamental features of signaling pathways in the immune system's T cells. In the course of these studies, he discovered message-relaying proteins called immunophilins (of the same family as FKBP12) and began to study the immunosuppressant drugs to which they bind.

Several years ago, Dr. Schreiber and Gerald Crabtree, Ph.D., of Stanford University conceived of the idea of engineering cells so that immunosuppressants could be used to turn an inserted gene on and off. One of the reasons that scientists have had trouble employing healthy genes to correct genetic defects is that there is no good way to control an implanted gene. This has limited gene therapy to diseases where control is not critical. Without this control, the body might make too much or too little of the necessary gene product. What Drs. Schreiber and Crabtree were exploring was a way to modify the molecular "switch" for a gene so that it could be controlled by drugs.

One possibility was to modify the gene for the desired product so that only a genetic switch that was not normally found in the body could turn it on. Then the researchers would attach parts of this switch to proteins that only a drug (in this case, rapamycin) could bring together. Without rapamycin, the switch would be off because the proteins would not associate with each other. When the proteins came together, the therapeutic gene product would be made.

The idea is bearing fruit. Recently, researchers at ARIAD Pharmaceuticals, a firm that has licensed Drs. Schreiber and Crabtree's idea, have succeeded in putting a modified human growth hormone gene and a modified, rapamycin-controlled, switching mechanism into human skin cells. Then they implanted the cells into mice and dosed the mice with rapamycin. The cells made the human growth hormone, with the amount made determined by the amount of rapamycin the mice were given.

In addition to the exciting possibilities it holds for gene therapy, the structural study also provides the first insights into the three-dimensional features of FRAP, which is a member of an important family of proteins that are involved in the control of cell division and in the development of cancer.


Choi J, Chen J, Schreiber SL, Clardy J. Structure of the FKBP12-Rapamycin Complex Interacting with the Binding Domain of FRAP. Science 1996;273:239-42.

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