METALLOPROTEASE DOCKED WITH TIMP--ANGIOGENESIS INHIBITOR

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DESCRIPTION (from the application): Progression of rheumatoid arthritis and other diseases depends upon angiogenesis. Angiogenesis is mediated by a proteolytic cascade involving matrix metalloproteinases (MMPs). Tissue Inhibitors of Metalloproteinases (TIMPs) suppress angiogenesis. Agents which mimic TIMP in inhibition of MMP-dependent angiogenesis but which are easier to prepare and deliver or which selectively inactivate key members of the matrix metalloproteinase family would make powerful therapeuticals for rheumatoid arthritis and other angiogenic diseases. Long-term efforts in mimicry of TIMP require knowing the three-dimensional structure of a TIMP/MMP complex. Recent results suggest hypotheses about the nature of the TIMP/MMP interface, requiring further evaluation: The high affinity of the complex may be explained by multiple contacts, more extensive than those of small molecule inhibitors of MMPs. Many of these contacts may be hydrophobic. TIMP may present contacts to the S-shaped, metal-binding loop of the MMP. The specific aims involve docking the NMR structures of human MMP-3 and the inhibitory domain of human TIMP-l, using NMR spectroscopy. This preliminary 3D model of the complex will be suitable for evaluating the hypotheses about the character of the interface. The steps to docking the structures by NMR require identification of the aliphatic H(1) and C(13) peak positions of each protein and interpretation of the intermolecular NOE spectra, reflecting the close contacts between metalloprotease and TIMP. Three-dimensional structure of the TIMP/MMP complex and insight into the character of its interface will serve as a template to stimulate long-range efforts to develop a mini-TIMP or other TIMP-mimicking agents to stifle angiogenesis.