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17 April 2014 12:48 pm ,
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Officials last week revealed that the U.S. contribution to ITER could cost $3.9 billion by 2034—roughly four times the...
An experimental hepatitis B drug that looked safe in animal trials tragically killed five of 15 patients in 1993. Now,...
Using the two high-quality genomes that exist for Neandertals and Denisovans, researchers find clues to gene activity...
A new report from the Intergovernmental Panel on Climate Change (IPCC) concludes that humanity has done little to slow...
Astronomers have discovered an Earth-sized planet in the habitable zone of a red dwarf—a star cooler than the sun—500...
Three years ago, Jennifer Francis of Rutgers University proposed that a warming Arctic was altering the behavior of the...
- 17 April 2014 12:48 pm , Vol. 344 , #6181
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Firming Up a Protein Grip
12 March 1999 7:00 pm
As molecular workers of the cell, proteins often do business with a handshake, temporarily grasping other molecules to pass on signals that order cells to grow or multiply. Now researchers have devised a new strategy to tighten or loosen the proteins' grip. The new technique, reported in the current Proceedings of the National Academy of Sciences, could boost the ability of drug researchers to reroute cell signaling and prevent the runaway growth of cancer cells.
For generations, biochemistry students have learned that molecules called ligands bind to a receptor or an enzyme like a key fits a lock. Many drugs mimic natural ligands, altering cell signaling by either jamming the lock or opening it better than the natural key. But many of the cell's growth signals are passed on by large protein ligands, which may bind to the target protein in several places over a large area. Long searches by legions of drug company workers have yielded few potential drugs, which are typically very small, that can block a much larger protein from signaling another protein.
The immune system has provided some inspiration for solving this conundrum. Immune system cells are activated when a small signaling ligand binds to a receptor within the cells, but the ligand is only weakly attracted. The solution is to use a large delivery protein (called FKBP52) to hand deliver the ligand to its receptor. Inspired by this strategy, the researchers--biochemist Gerry Crabtree, chemist Thomas Wandless, and their colleagues at Stanford University--wanted to try hand-delivering a ligand to block a protein fragment called SH2 found on many growth-signaling enzymes.
The team enlisted FKBP52 to carry a small, weakly binding drug called a tetrapeptide to the SH2 fragment. The researchers attached the tetrapeptide to FKBP52 with a second protein that bound to both molecules. Using a radioactive binding assay, the team showed that the delivery protein helped the drug bind three times more tightly to SH2 than it normally does, probably because the delivery protein itself also grasps the target protein. A second delivery protein, called FKBP12, actually weakened the interaction. The combination of small ligand and delivery protein could block signaling between pairs of proteins like growth factors and receptors better than a small ligand alone.
Other experts say that the technique should boost drug design efforts and help scientists fine-tune cell signaling molecules. "I think it's an idea of great generality because there are many protein surfaces you might be able to borrow," says organic chemist Jon Clardy of Cornell University. "It's a very unique approach to a long-standing problem."