Structural Genomics: A Special Emphasis on Membrane Proteins

Drug discovery based on structural knowledge has proven useful as several structure-based medicines are already on the market. Structural genomics aims at studying a large number of gene products including whole genomes, topologically similar proteins, protein families and protein subtypes in parallel. Particularly, therapeutically relevant targets have been selected for structural genomics initiatives. In this context, integral membrane proteins, which represent 60–70% of the current drug targets, have been of major interest. Paradoxically, membrane proteins present the last frontier to conquer in structural biology as some 100 high resolution structures among the 30,000 entries in public structural databases are available. The modest success rate on membrane proteins relates to the difficulties in their expression, purification and crystallography. To facilitate technology development large networks providing expertise in molecular biology, protein biochemistry and structural biology have been established. The privately funded MePNet program has studied 100 G protein-coupled receptors, which resulted in high level expression of a large number of receptors at structural biology compatible levels. Currently, selected GPCRs have been purified and subjected to crystallization attempts