Fell-Muir Lecture: Metalloproteinases: from demolition squad to master regulators

Two families of the Metzincin clan of metalloproteinases, the matrix metalloproteinases and the disintegrin metalloproteinases have attracted much attention as important effectors of cellular interactions with their environment. They appear to play significant roles in the modulation of components of the extracellular matrix, matrix and cell receptors, as well as the cytokines and growth factors and their receptors. Such functions at the 'cutting edge' of cell biology puts these enzymes in pivotal roles in the orchestration of the rapid response of cells to their environment, acting as key switches between different signalling pathways. Inevitably such enzymes should be regarded as suitable targets for therapeutic approaches to many diseases where such pathways become dysregulated. A major challenge to the development of direct inhibitors of catalysis has been the broad structural similarity of the Metzincin catalytic site. More detailed knowledge of active site structures has helped to some extent to resolve the development of more specific chemical inhibitors and selected enzymes are now being targeted. An alternative strategy is the consideration of the role of the extracatalytic domains that are determinants of specificity at a variety of levels. Dissecting the relationships between structure and function of these interaction sites is allowing the development of new approaches to inhibition of enzyme function. Antibodies are proving useful tools in this respect and may pave the way to a novel biologics approach to disease therapy.