EMBL researchers discover how customised drugs can switch off stuck transmission in cancer-causing protein

Heidelberg 25 January 2002Researchers at the European Molecular Biology Laboratory (EMBL) have produced a detailed diagram of a protein linked to leukaemia which gives researchers a head start in designing drugs to combat the disease. Italian researcher Giulio Superti-Furga and his colleagues have generated the diagram of the cancer-causing molecule. Their report appears in the recent issue of the journal Cell.

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Scientists developing drugs to combat disease typically work by finding drugs which work by blocking the activity of a particular molecule in a cell, like putting a lock over a switch. Now an EMBL team headed by Italian researcher Giulio Superti-Furga has produced a detailed diagram of the protein Abl, which is linked to certain forms of leukaemia. Using the information provided by the diagram, researchers hope to custom drug design to block specific cellular "switches".

The molecule, a protein called Abl, is produced in all human cells, but some people acquire a defect in the genetic blueprint for the molecule, causing their bodies to create a malformed version called BCR-Abl, which is linked to certain forms of leukaemia. One of the main roles of the Abl protein is to send messages telling other molecules to divide. Normally, the number of times this message is sent is limited, but BCR-Abl and other defective forms of the protein get "stuck" in transmission mode, leading to a very high rate of cell division and thus cancer.

"Abl needs to be switched off", explained Giulio Superti-Furga, "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. We have now discovered that there is an internal switch which 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 cannot stop sending signals." The discovery is a significant starting point in designing drugs to treat leukaemia.

The key thing that Dr. Superti-Furga and colleagues Helma Pluk and Karel Dorey discovered is that this clamp lies in a part of the molecule which is distant from the machinery which actually transmits the 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 found the clamp by creating artificial versions of Abl missing certain parts, and examining the molecule's transmitting capabilities in a test tube. When they removed a cap section which connects itself to two major sub-structures of the molecule, they discovered that Abl could no longer be shut down.

"BCR-Abl does not have this cap, so other parts of the molecule probably move out of their proper positions", Dr. Superti-Furga stated. "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.

The European Molecular Biology Laboratory is a basic research institute funded by public research monies from 16 member states, including most of the European Union, Switzerland, and Israel. Research at EMBL is conducted by approximately 80 independent groups covering the spectrum of molecular biology. The Laboratory has five units: the main Laboratory in Heidelberg; Outstations in Hinxton at the European Bioinformatics Institute, Grenoble, and Hamburg; and an external research programme in Mouse Biology in Monterotondo near Rome.

The corner-stones of EMBL's mission are to perform basic research in molecular biology, to train scientists, students and visitors at all levels, to offer vital services to scientists in the member states, and to develop new instruments and methods in the life sciences. The Laboratory also sponsors an active Science and Society programme.


Leslie Versweyveld

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