文章基本信息

标题：Crystal structure of the catalytic domain of human tumor necrosis factor-α-converting enzyme
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作者：Klaus Maskos ; Carlos Fernandez-Catalan ; Robert Huber 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：1998
卷号：95
期号：7
页码：3408-3412
DOI：10.1073/pnas.95.7.3408
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Tumor necrosis factor- (TNF) is a cytokine that induces protective inflammatory reactions and kills tumor cells but also causes severe damage when produced in excess, as in rheumatoid arthritis and septic shock. Soluble TNF is released from its membrane-bound precursor by a membrane-anchored proteinase, recently identified as a multidomain metalloproteinase called TNF-converting enzyme or TACE. We have cocrystallized the catalytic domain of TACE with a hydroxamic acid inhibitor and have solved its 2.0 A crystal structure. This structure reveals a polypeptide fold and a catalytic zinc environment resembling that of the snake venom metalloproteinases, identifying TACE as a member of the adamalysin/ADAM family. However, a number of large insertion loops generate unique surface features. The pro-TNF cleavage site fits to the active site of TACE but seems also to be determined by its position relative to the base of the compact trimeric TNF cone. The active-site cleft of TACE shares properties with the matrix metalloproteinases but exhibits unique features such as a deep S3' pocket merging with the S1' specificity pocket below the surface. The structure thus opens a different approach toward the design of specific synthetic TACE inhibitors, which could act as effective therapeutic agents in vivo to modulate TNF-induced pathophysiological effects, and might also help to control related shedding processes.