Tailoring TIMPs for Selective Metalloproteinase Inhibition
Members of the metzincin clan of zinc endopeptidases (metalloproteinases, MPs) are key players in the proteolytic modification of cell surface and extracellular matrix proteins which are the bases of many cellular responses. They are regulated by a small family of endogenous inhibitors, the tissue inhibitors of metalloproteinases (TIMPs). TIMPs were originally identified as natural regulators of the matrix metalloproteinases (MMPs), but they exhibit distinctive structural features and biochemical properties, suggesting that each has specific roles in vivo. Interactions with the disintegrin metalloproteinases, ADAMs and ADAMTS s, appear to be even more selective. The ability of these proteins to inhibit the MPs is largely due to the interaction of a wedge-shaped ridge on the N-domain which binds within the active-site cleft of the target proteinase. Apart from structural studies, features of the specific interactions between individual TIMPs and MPs have been ascertained by a combination of engineering and kinetic studies. This has also led to the concept of redesigning or ‘tailoring’ TIMPs for more specific anti-MP functions, as potential tools for interrogation of biological systems, and as therapeutic agents in diseases such as cancer with a strong MP involvement. This chapter will review current progress towards this goal.
KeywordsCatalytic Domain Protein Data Bank Tissue Inhibitor Disulphide Bond Brookhaven Protein Data
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