For the first time, three-dimensional images of protein being paralysed by the poison curare have been made by researchers of the Laboratory for Structural Neurobiology at K.U.Leuven. Curare has a paralysing effect and the poison's active chemical component is used in lung surgery. To date, however, scientists did not know how exactly it works. 3D images have now opened new perspectives for the development of medications against sleeping disorders, tobacco addiction and muscle diseases.
The human cell membrane -- the wall of a living cell -- houses more than 7,000 proteins, but researchers have only managed to identify the structure and function of 27 of these. Ion channels are an important class of membrane proteins that are responsible for communication. The Laboratory for Structural Neurobiology at K.U.Leuven has mapped the three dimensional structure of ion channels.
Professor Ulens, director of the lab, explains what the 3D images of curare mean: "We are locksmiths who examine on an atomic scale how a key -- the poison -- fits the lock of a door -- the ion channel -- and how the key keeps the door locked. Some kinds of poison only fit one lock, but curare is a passkey that can close various ion channels. Using 3D knowledge of the structure of this lock, researchers are able to develop passkey medications for a class of disorders. Or they can develop a specific medication for one disorder, such as tobacco addiction for example, as nicotine affects one specific ion channel.
Ion channels are actually switches. The proteins are shaped like microscopic pores that can open and close. Ions -- charged particles -- flow in or out of the cells through them. Poisons are able to disrupt the communication between cells in the body by blocking ion channels. Curare is the poison the indigenous populations of the Amazon use while hunting. They apply the poison to their arrows in order to paralyse their prey. Tubocurarine -- the active chemical component of curare -- paralyses the muscles and can shut down respiration, resulting in death.
The fact that so little is known about membrane proteins is related to the fatty environment of the cell membrane. In X-ray crystallography -- the standard technique to study proteins -- crystals of proteins are grown in water and then X-rayed in order to expose and examine their structure. Forming crystals of fatty membrane proteins is difficult, however. Professor Ulens explains how his team was able to circumvent this problem: "For the past ten years, researchers were forced to get in through the backdoor: a chemical copy of a section of ion channel. Chemically similar, but not porous. As a result, the formation of crystals was much easier. For the first time, our lab has applied the back entrance to the ion channel, which is sensitive to curare. We now have an image of how this class of ion channels recognises chemical substances."
Ulens hopes to use these results to contribute to the rational development of medications: "In the past, the pharmaceutical industry developed medications by releasing hundreds of thousands of substances into ion channels. If a certain substance caused a reaction, it would be tested on patients -- a system of trial and error. Our research results in the more goal-oriented development of medications: by acquiring insight into the three-dimensional structure of an ion canal, specific medications that bind to the protein can be developed."
- Marijke Brams, Anshul Pandya, Dmitry Kuzmin, René van Elk, Liz Krijnen, Jerrel L. Yakel, Victor Tsetlin, August B. Smit, Chris Ulens. A Structural and Mutagenic Blueprint for Molecular Recognition of Strychnine and d-Tubocurarine by Different Cys-Loop Receptors. PLoS Biology, 2011; 9 (3): e1001034 DOI: 10.1371/journal.pbio.1001034
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