Matrix metalloproteases: variations on a theme.
The family of proteins called matrix metalloproteinases (MMPs) are a class of structurally related proteins that are collectively responsible for the metabolism of extracellular matrix proteins. These zinc and calcium dependent enzymes, which include the collagenases, stromelysins and gelatinases, are involved in normal tissue remodelling processes such as wound healing, pregnancy and angiogenesis. Under physiological conditions, in addition to the regulated proteolyses of inactive precursors to the active form, the degradative nature of these enzymes are precisely controlled by endogenous inhibitors (TIMPs). The excess syntheses and production of these proteins lead to the accelerated matrix degradation associated with diseases such as arthritis, cancer and multiple sclerosis. The MMPs have therefore proved to be attractive targets for structure based drug design. The pursuit of low molecular weight inhibitors of these proteins have encouraged structural studies on several members of family, so that the molecular details of enzyme-inhibitor interactions of the MMPs have become available. These studies provide insights into the basic structural framework of the MMP superfamily and reveal characteristics which promote specificity between individual members. The analyses of the three dimensional structure of the MMPs in the context of their primary sequence and the design and selectivity of low molecular weight inhibitors of the superfamily is the subject of this review.
Borkakoti
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Roche Discovery Welwyn, Welwyn Garden City, Herts, U.K. neera.borkakoti@roche.com
D000595:Amino Acid Sequence; D000818:Animals; D020134:Catalytic Domain; D016384:Consensus Sequence; D005109:Extracellular Matrix / Q000378:metabolism*; D005260:Female; D006801:Humans; D008666:Metalloendopeptidases / Q000737:chemistry* / Q000378:metabolism*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D018919:Neovascularization, Physiologic; D011247:Pregnancy; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D016415:Sequence Alignment; D014945:Wound Healing
D008666:Metalloendopeptidases