Many of today’s medicines were discovered by trial and error: a substance is found which helps alleviate the symptoms of a disease, and it may take years before scientists really understand how it works. Typically they find that a drug has its effects by attaching itself to a particular molecule in a cell and blocking part of its activity, the way you might prevent someone from turning a light on or off by putting a lock over the switch. Scientists now hope to take the opposite approach, and custom-design drugs to block specific switches. To do so, they will need precise “technical diagrams” of the molecules they want to lock up.
Now the Italian researcher Giulio Superti-Furga and his colleagues at the European Molecular Biology Laboratory (EMBL) have produced such a diagram of a cancer-causing molecule, and their work gives researchers a good idea of how to go about designing drugs. Their report appears in the current issue of the journal Cell.
The molecule, a protein called Abl, is produced in all human cells. Some people acquire a defect in the genetic blueprint for this molecule, causing their bodies to create a malformed version called BCR-Abl. For years researchers have known that this defective molecule is linked to forms of the deadly disease leukemia.
Abl has important jobs to perform within cells. One of its chief roles is to get information from proteins and pass it on to other molecules – like a radio operator who receives a message telling him to turn on an alarm. If Abl is defective, it might not hear incoming messages, or it might continually send off alarms, even when it hasn’t been told to do so.
One of the messages that Abl transmits tells the cell, “It’s time to divide.” Normally this signal shouldn’t be sent too often, but BCR-Abl and other defective forms of the protein are stuck in transmission mode, leading to a very high rate of cell division and thus cancer.
“Abl needs to be switched off, and one of the chief questions that people have had is whether other molecules are needed to throw the switch, or whether Abl can turn itself off,” says Giulio Superti-Furga. “We’ve now discovered that there is an internal switch that allows it to shut itself down. BCR-Abl is missing an important structural piece of the protein, a sort of clamp that holds things in the right places, and the molecule can’t stop sending signals.”
The key thing that Superti-Furga and colleagues Helma Pluk and Karel Dorey have discovered is that the clamp lies in a part of the molecule quite distant from the machinery that actually transmits signals. Clinical trials are currently being performed with a drug called STI571, which appears to directly block the transmission machinery, but some patients are able to develop resistance to the drug. This might be because the real switch is still turned on.
The EMBL researchers discovered the clamp by creating artificial versions of Abl missing certain parts, and then examining the molecule’s transmitting capabilities in the test tube. When they removed a cap section that connects itself to two major substructures of the molecule, they discovered that Abl could no longer be shut down.
“BCR-Abl doesn’t have this cap, so other parts of the the molecule probably move out of their proper positions,” Superti-Furga says. “If you imitate this by removing the cap from the normal form of Abl, or preventing the cap from clamping onto the proper parts of the molecule, the switch gets frozen.”
This explains why several roads might lead to the same result – cancer. Even if the cap structure is present, other molecules might interfere with it and break the internal switch. By showing that the cap is essential in Abl’s switch, the researchers have provided a very good place to start in designing new drugs for this specific type of cancer.
Autoinhibition of c-Abl. Helma Pluk, Karel Dorey, and Giulio Superti-Furga. Cell, Vol. 108, 1-20, Jan. 25, 2002.
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