Hot spot in medicine research
Researchers in the National Centre of Competence in Research (NCCR) "Structural Biology – Molecular Life Sciences: Three dimensional Structure, Folding and Interactions" have solved the mystery of one of the key elements of the living cell: the structure of the ABC transporters. Today it is therefore acknowledged as one of the best centres in the world for structural biology.
"I've always been fascinated by membrane proteins, specifically because of the diversity of their function," comments Kaspar Locher. He is Professor at the Institute for Molecular Biology and Biophysics at the ETH Zurich and member of the steering committee of the NCCR "Structural Biology ". Kaspar Locher is one of the world's most eminent specialists on ABC transporters, a particularly versatile type of membrane protein, omnipresent in the living world and therefore also in humans. These molecules are currently a real hot spot in medicine research.
Kaspar Locher's breakthrough took place three years ago. In a paper published by the English science magazine, Nature, Kaspar Locher first described the structure of these ABC transporters in a special configuration of major scientific relevance. "The publication attracted worldwide attention because I revealed a result that had been sought after for some time," comments Kaspar Locher. "An advance like this only happens to you once in a decade." His publication in Nature made quite a sensation in the research community. Not only did Kaspar Locher reveal what this type of membrane looks like when it is doing its work, but thanks to meticulous research, he also proved that the ABC transporter structure outlined by an American competitor back in 2001 was faulty. The entire scientific community stood corrected.
Kaspar Locher acknowledges that the support from the NCCR "Structural Biology" is extremely valuable. "The NCCR provides long-term funding, which is crucial for high risk projects like explaining the structure of membrane proteins. In this type of research where it is entirely possible that two years of work results in nothing."
So what are membrane transport proteins really about? They are components of the cell membrane and work like valves that carry vital substances to the cell interior and back out again. All ABC transporters need energy to function and it is the ATP molecule, which acts as the cell’s fuel. These are characterized by an ATP-binding site. This is also how they get their name (ATP Binding Cassette). ABC transporters are thought to play a key role in how well or poorly medicines work. Today, for instance we know they are responsible for cancer cells resisting a range of medicines.
Yet the precise way in which they work is virtually unknown. To achieve a better understanding, more knowledge of what the proteins look like when they are at work is required. For instance, what does the ABC transporter look like when the figurative valve is opened and closed to the cell interior? When it is carrying a substance and when the valve is opened outwards? Unfortunately, membrane proteins are among the most difficult substances in the living world to study. The reason is that in order to establish the exact structure of the proteins, the researchers must make them regularly form crystals which are then x-rayed in sequence. However, it is difficult to crystallise membrane proteins because they are composed of both water-soluble and fat-soluble components. However, these types of hurdles only serve to encourage Kaspar Locher in his research. "I simply can’t resist a challenge like this; I simply had to solve the puzzle."
Kaspar Locher's experiments with the ABC transporter were successful. In his Nature article in 2006, he was able to illustrate the structure of these molecular valves at a crucial stage – i.e. at the point at which they bonded with an ATP molecule and therefore with their source of energy.
Today Kaspar Locher ranks as one of the most renowned structural biologists in the world. His publications are often cited. It comes as no surprise that top research funding agencies and international corporations are interested in his findings. Incidentally, last year the barely 40 year-old Kaspar Locher also received the Federations of the Societies of Biochemistry and Molecular Biology (FEBS) award for the best publication by a young researcher, or the FEBS Letters Young Scientist Award. In Kaspar Locher's opinion the NCCR "Structural Biology" has increased enormously the importance and reputation of all the groups working in Zurich. "As so many outstanding researchers now work here in Zurich, international recognition is automatically very high. Today we are acknowledged as one of the best centres in the world for structural biology."