XRAY CRYSTALLOGRAPHIC STUDIES OF DRUG DESIGN TARGETS

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This proposal describes two projects involving structure determinations of proteins that are drug design targets. One of these, Microsomal Triglyceride Transfer Protein (MTP), is a protein involved in the transport of lipids and phospholipids between membranes in the liver and intestine. It is proposed that inhibitors of MTP will block the uptake of cholesterol in the liver and intestine and provide dramatically more effective cholesterol lowering therapies. The other project involves _-glucuronidase, which cleaves _-glucuronic acid from glycosaminoglycans and is an essential enzyme for the normal turnover of these extracellular matrix components. _-glucuronidase and other lysosomal enzymes are released into the synovial fluid in inflammatory joint diseases such as rheumatoid arthritis where they contribute to the symptoms. Efforts are underway to cocrystallize both of these enzymes in the presence of inhibitors as part of an interactive drug design project.