Genome sequencing exercises have revealed that about 30% of all cellular proteins are membrane located or associated. The study of the structures and functions of these membrane proteins has proven to be extremely difficult as is indicated by the fact that the unique structures of more than 20,000 soluble proteins have been solved compared with fewer than 400 of membrane transport and channel proteins. These membrane proteins perform crucial functions for every biological cell, ranging from signal transduction, generation of metabolic energy, transport of ions and essential solutes to the inside, excretion of waste products to the outside, and communication with the external milieu. The activities of a significant number are implicated in disease, and, being readily accessible to the outside of a cell, they are the perfect targets for compounds that can modify their activities. In view of the rapidly increasing resistance of microorganisms against antibiotics, and of cancer cells against chemotherapy, the development of new drugs is urgently needed since such diseases affect hundreds of millions of human beings. In order to be able to design these drugs, understanding the molecular structure and the mechanism of action of relevant target membrane proteins is of immense value. That has proven to be a very difficult requirement. General protocols to obtain sufficient large quantities of solubilized stable membrane proteins that yield crystals diffracting to a high resolution are not available. Each protein requires its own protocol, which explains the slow progress in understanding the structure and function of these proteins.
The Seventh Framework Programme of the European Community supported with 12 million Euros the European Drug Initiative on Channels and Transporters (EDICT) project for a period of four years. The aim of EDICT was the determination of the structure-function relationships of clinically significant membrane protein channels and transporters with special emphasis on initial drug design and screening. This project brought together prominent European research groups working on membrane proteins: Structural biologists, molecular geneticists, physiologists, pharmacologists, computational chemists, bioinformatics specialists and industrial partners. No fewer than 25 universities and research institutes in 13 countries from all over Europe as well as Israel and the Russian States plus two industrial partners, comprising a total of 37 research groups, participated in EDICT. The project was coordinated by Prof. Peter J. F. Henderson of the University of Leeds, UK and chaired by Prof. Sir John Walker, FRS, of the MRC Mitochondrial Biology Unit, Cambridge, UK.
EDICT started in 2008 and formally ended in July 2012. Due to the intense interactions between the partners, the results obtained in EDICT are impressive. Advanced tools have been developed and applied for the over-expression, solubilization, reconstitution in artificial membranes, functional analysis, crystallization, structural analysis and ligand design, and these tools have been exchanged broadly between the partners and published. More than 20 high resolution structures of 16 membrane proteins have already been determined while the analyses of several more membrane proteins are at an advanced stage in the pipeline. Potential modulators or inhibitors of function have been tested for most of these proteins with several promising hits already under development.
The current issue of Molecular Membrane Biology devoted to EDICT and edited by EDICT partners Bernadette Byrne and Roslyn Bill, clearly demonstrates the wide variety of expertise and innovative methodologies required to tackle effectively extremely difficult problems such as membrane proteins. The nine high-quality articles in this special issue, together with a further 10 in an upcoming issue, illustrate that scientific support from the European Community can substantially and successfully contribute to European fundamental biological sciences and thereby provide a solid foundation for improving European Health.
EDICT Scientific Advisory Board
Wim G. J. Hol
University of Washington, Seattle, WA, USA
Wil N. Konings
University of Groningen, Groningen, The Netherlands