Credit: Richard Gillilan/Cornell University

Scientists led by a Cornell chemist have determined the structure of a key protein that binds to a powerful immunosuppressive agent, opening the door to improved cancer treatments and human gene therapy.

The protein, called FRAP, binds to one side of rapamycin, a small, naturally occurring molecule that is known to shut down the immune system. The other side of rapamycin binds to another protein called FKBP12. When all three are bound together, the cell cycle is shut down.

"This is a fascinating story of cell signaling and how information is used and eventually may lead to making a better immunosuppressive drug," said Jon C. Clardy, Cornell professor of chemistry who led the work. "It's important also in understanding how proteins interact and how that information can be used to control genes and other cellular processes."

Clardy and co-authors Jungwon Choi, former Cornell postdoctoral associate now in Korea, and Jie Chen and Stuart Schreiber of Harvard University, reported their work today (July 12, 1996) in the journal Science. Their work was funded by the National Institutes of Health.

FRAP appears to be an important regulatory protein and it is related to a growing family of such proteins, Clardy said. Acting as a sort of checkpoint during the cell cycle, this protein halts the cycle in a very specific place. "It's like slamming the brakes on and the motor's still running. Everything comes to a halt," he said.

That effect means that immune cells, which may be mounting a response to certain treatments, get stopped in their tracks so that therapies can be administered. But also, it means that the molecule can perhaps stop cancer cells from dividing as well. "It causes all cells to arrest. It's a very interesting effect," Clardy said.

The structure also has implications in gene therapy. "It's not that hard to introduce new genes. What's hard is turning them on," Clardy said. "Small molecules such as rapamycin may be a good technology for getting a gene to turn on." Such uses may include targeting a defective gene and replacing it with a good gene.

The researchers used supercomputer resources of the Cornell Theory Center to make simulations of the structure of the molecule binding with the two proteins. Richard Gillilan, Cornell visualization specialist, produced pictures to illustrate the mechanism. Data for determining the structure were collected using the X-ray source at CHESS, the Cornell High Energy Synchrotron Source.

The rapamycin molecule, discovered 20 years ago in a microbe from a soil sample on Easter Island, is "exquisitely shaped" to fit the two proteins, Clardy added. Clardy's group had earlier determined the structure of rapamycin and FK506, another potent immunosuppressive agent bound to FKBP12. Following the cellular pathway, they found that rapamycin and FKBP12 bind together and look for another protein to work with -- the protein that ultimately turned out to be FRAP. Rapamycin alone would not bind to FRAP; it needs FKBP12 first. The current report describes how the whole system works.

"Our data provide a structural framework for understanding the rapamycin-based dimerization of FKBP12 and FRAP," the authors write in their report. "Because rapamycin-induced protein dimerization can form the basis for regulating gene transcription and other cellular processes, such structure-based modifications of the interaction might have important practical consequences. The structure also provides insights into structural features and possible regulation of (this) family of proteins."