Structural Studies on MMPs andTIMPs Wolfram Bode and Klaus Maskos

The proteolytic activity of the matrix metalloproteinases (MMPs) involved in extracellular matrix degradation must be precisely regulated by their endogenous protein inhibitors, the tissue inhibitors of metalloproteinases (TIMPs). Disruption of this balance results in serious diseases such as arthritis and tumor growth and metastasis. Knowledge of the tertiary structures of the proteins involved is crucial for understanding their functional properties and interference with associated dysfunctions. Within the last few years, several three-dimensional structures became available showing the domain organization, the polypeptide fold and the main specificity determinants of the MMPs. Complexes of the catalytic MMP domains with various synthetic inhibitors enabled the structure based design and improvement of high-affinity ligands, which might be elaborated into drugs. Very recently, structural information also became available for some TIMP structures and MMP-TIMP complexes, which allowed to derive the structural features governing the enzyme-inhibitor interaction. A multitude of reviews surveying work done on all aspects of MMPs and TIMPs appeared within recent years, but none of them concentrating on the three-dimensional structures. This review is considered to close this gap.