News Release

Uncovering structure of cellular switch could aid design of cancer-fighting drugs

Peer-Reviewed Publication

Cornell University

ITHACA, N.Y. -- Cornell University cancer researchers have revealed the molecular structure of a protein complex believed to influence the malignant transformation of cells, setting the stage for development of unique tumor-blocking drugs.

The structure of Cdc42, a molecular "switch" that turns on essential pathways in both normal and cancerous cells, and GDI (for guanine nucleotide-dissociation inhibitor), a key regulator of the Cdc42 switch, is reported in the February issue of the journal Cell (vol. 100, pp. 345-356).



Ribbon diagram of the Cdc42/GDI complex.

Full size image available through contact

"Knowing the precise, atom-by-atom structure and shape of this molecular switch (Cdc42), and the structure of other cellular proteins that regulate its activity, should eventually allow us to identify and even design small molecules that alter Cdc42 function and thereby prevent the Ras oncogene from inducing the malignant state," explains Richard A. Cerione, professor of molecular medicine in the College of Veterinary Medicine and professor of chemical biology in the College of Arts and Sciences at Cornell. The Ras oncogene is a gene that can cause cancer when it is altered.

The structure of the protein complex was mapped at MacCHESS, Cornell's high-energy synchrotron source, where the scientific technique called X-ray crystallography reveals the three-dimensional arrangement of atoms in molecules by bombarding them with intense bursts of X-rays. A "ribbon" diagram of the Cdc42/GDI complex is printed on the cover of the journal. Co-authors of the report, along with Cerione, are Gregory R. Hoffman, a Cornell graduate student in biophysics, and Nicolas Nassar, a postdoctoral associate.

The mammalian Cdc42 protein originally was purified and cloned at Cornell by researchers in Cerione's laboratory in 1990. Cdc42 is believed to play a dual role, alternating as an essential protein for normal cell growth and as a switch that allows protein from a mutated Ras oncogene to cause cancer. Many of the current strategies for intervening against cancer are directed at the Ras protein. The Cornell biochemists believe that, given the essential function of Cdc42 in Ras-induced malignant transformation, it should be possible to block signals that lead to cancer by modulating Cdc42 activity.

"We are not ready to start designing drugs yet," Cerione cautions. "This has been an extremely difficult biological problem. Just obtaining sufficient amounts of the proteins in functional form and figuring out how to crystallize them was a formidable challenge. The achievement is a real tribute to Greg and Nico's talents and dedication," he says of his scientific colleagues.

However, Cornell University is one of the few institutions in the world with the scientific capability to move a discovery from the basic-biology stage to the determination of molecular structure, the design of drugs and finally to clinical trials, observes Douglas D. McGregor, associate dean for research in the College of Veterinary Medicine. He points to Cornell's expertise in chemical biology in the College of Arts and Sciences, the universitywide Genomics Initiative and MacCHESS, as well as to the veterinary college with its Molecular Medicine and Comparative Cancer programs, the hospital clinics where animal patients with cancers are treated and the facilities for conducting clinical trials of new therapies in animal models.

Studies of the Cdc42/GDI complex were supported by grants from the National Institutes of Health and the international Human Frontiers of Science Program.

Related World Wide Web sites: The following sites provide additional information on this news release.

-- Chemistry and Chemical Biology at Cornell: http://www.chem.cornell.edu/

-- Veterinary Medicine at Cornell: http://www.vet.cornell.edu/

-- Cerione laboratory: http://www.vet.cornell.edu/public/pharmacology/TheDepartment/Rick_Cerione/frame_Rick_Cerione.html

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