Scientists have taken a significant leap forward in understanding the complex ways that molecules work together in cells. The work of the Structural & Computational Programme at EMBL-Heidelberg, in collaboration with Cellzome AG, appears in the current issue of the journal Science (March 26, 2004).
Although scientists already know a lot about single molecules, they know very little about how they are assembled into larger molecular complexes or "machines" and how these machines work together to create a complete, functioning cell. The problem is like trying to assemble a puzzle with billions of pieces– with only the shapes of some pieces to go on.
"What we all aim for is a complete molecular anatomy of the cell – to understand the big picture," says group leader Rob Russell, "That means finding out what machines are present in each part of the cell, what molecules make them up, and how they interact with each other."
One of the best ways to start a puzzle is to sort the pieces into sensible piles. That was extremely difficult until two years ago, when scientists from Cellzome and EMBL identified the components of hundreds of molecular machines in yeast cells.
"The information gave us more than a comprehensive list of the 'pieces' of protein machines – it also suggested intriguing connections between them," comments Giulio Superti-Furga, Senior Vice President of Cellzome AG. "So the next step was to understand how they interact and work together."
Machines can be seen as fuzzy objects under the electron microscope, but the resolution isn't high enough to reveal how single components fit together inside the complex. Patrick Aloy, from Rob Russell's group, combined electron microscopy images (taken by the EMBL Group of Bettina Boettcher) with data from other experiments to find out how the shape and chemistry of single proteins allow them to fit together.
Computer methods developed by Aloy and Russell allowed them to find likenesses between different machines – if the shapes of two molecules are very similar to a pair known to interact in another complex, they are likely to fit together in the same way. Building upwards from such pairs, the researchers were sometimes able to obtain a diagram for a machine. "This gave us a way of bridging the resolution gap between fuzzy pictures of cell machines and more detailed atomic pictures of their individual parts," Aloy comments.
"Once we have an assembly plan for an individual machine, we know what parts of the molecules would be on the outside surface, available for interaction with other complexes," Russell explains. "Then we could go through the pair-wise matching procedure again to see if we can connect machines to form a network. We then start to get an idea of what large parts of the cell look like."
Several groups in the Structural and Computational Biology Programme at EMBL are now combining efforts to study complexes and cellular structures using computational and experimental techniques.
"This study has built a solid framework for further research with the great advantage that the whole is greater than the sum of its parts: new experiments will improve it continuously", Aloy says. "The number of machines that we can place into the network will increase exponentially, providing an ever more complete molecular anatomy of the cell."
The European Molecular Biology Laboratory is a basic research institute funded by public research monies from 17 member states, including most of the EU, 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, and Outstations in Hinxton (the European Bioinformatics Institute), Grenoble, Hamburg, and Monterotondo near Rome. The cornerstones 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. EMBL's international PhD Programme has a student body of about 170. The Laboratory also sponsors an active Science and Society programme. Visitors from the press and public are welcome.
About Cellzome AG
Cellzome is a drug discovery company building an R & D pipeline in chronic diseases, with a primary focus on Alzheimer's Disease. Cellzome is leveraging its powerful drug proteomics engine to generate an ongoing pipeline, both for in-house drug development and through partnership. Cellzome's unique combination of chemical proteomics and pathway expansion enables more efficient drug discovery by focusing on the interface between validated disease pathways, tractable medicinal chemistry and druggable targets. This approach is being applied to enable the efficient discovery of new medicines for chronic human diseases.
An international team of approximately 100 employees based in Heidelberg, Germany and London, UK, is building a strong pipeline of drug candidates.Founded at the EMBL in May 2000, Cellzome has combined scientific leadership with experienced pharmaceutical management. http://www.cellzome.com.
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