Human Collagenase-3 (MMP-13, matrix metalloproteinase)

Human collagenase-3 (MMP-13) is a member of the matrix metalloproteinase (MMP) family which include the collagenases, stromelysins and gelatinases. The MMPs are involved in the degradation of the extracellular matrix which is associated with normal tissue remodeling processes such as pregnancy, wound healing, and angiogenesis. The MMPs have also demonstrated activity against cell surface and other pericellular non-matrix proteins further contributing to their cellular function. The MMP family consists of more than 25 enzymes where major discriminating factors are substrate preference (collagens, fibronectin, elastin, gelatins, etc.), domain structure and sequence alignment. The MMPs are modular proteins where a signal peptide, propeptide and catalytic domain are common to the entire family. Additional domains observed in MMP structures include fibronectin type II-like, hemopexin-like, vitronectin-like and transmembrane domains. Fundamental to the structural integrity and activity of MMPs is the presence of both zinc and calcium in the protein’s structure. The active site zinc performs a critical function for both substrate binding and cleavage. Correspondingly, the design of MMP inhibitors has generally targeted the catalytic domain and active site zinc. The isolated catalytic domain maintains its general endopeptidase function but does not exhibit activity against its natural substrate. This is attributed to the absence of the hemopexin-like domain which is involved in substrate recognition and binding. The MMPs are a highly active set of targets for the design of therapeutic agents for the disease areas of arthritis and oncology. The MMPs have also been associated with multiple sclerosis, periodontitis, stroke, inflammatory bowel disease and cardiovascular disease.  MMP expression and activity is highly controlled because of the degradative nature of these enzymes. The apparent loss in this regulation results in the pathological destruction of connective tissue and the ensuing disease state. MMP-13 was recently identified on the basis of differential expression in normal breast tissues and in breast carcinoma. In addition its expression has been reported in squamous cell carcinomas of the larynx, head and neck and HCS-2/8 human chondrosarcoma cells and during fetal ossification and in articular cartilage of arthritic patients. There have been a number of X-ray and NMR structures solved for the catalytic domain of MMPs complexed with a variety of inhibitors. There is a close similarity in the overall three-dimensional fold for these proteins consistent with the relatively high sequence homology (> 40%). Despite this similarity in the MMP structures there is distinct substrate specificity between these enzymes indicative of specific biological roles for the various MMPs and a corresponding association with unique disease processes. One example of this potential specificity is the over-expression of MMP-13 in breast carcinoma and MMP-1 in papillary carcinomas. Therefore the current paradigm in the development of MMP inhibitors is to design specificity into the structures of the small molecule instead of developing a broad spectrum MMP inhibitor. The rational behind this approach is that an inhibitor specific for the MMP uniquely associated with a disease process may potentially minimize toxic side effects. Comparison of the various MMP structures has identified a significant difference in the size and shape of the S1’ pocket. This structural difference across the MMP family provides an obvious approach for designing specificity into potent MMP inhibitors by designing compounds that appropriately fill the available space in the S1’ pocket while taking advantage of sequence differences.

Also see the MMP-1 web page

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