Crystal structure of the catalytic domain of human tumor necrosis factor-α-converting enzyme
Crystal structure of the catalytic domain of human tumor necrosis factor-α-converting enzyme
复制标题
DOI：
10.1073/pnas.95.7.3408
复制
发表时间：
1998-03-31
影响因子：
11.1
通讯作者：
Bode, W
中科院分区：
文献类型：
--
作者：
Maskos, K;Fernandez-Catalan, C;Bode, W
肿瘤坏死因子-α（TNF α）是一种细胞因子，可诱导保护性炎症反应并杀死肿瘤细胞，但当过量产生时也会导致严重损伤，如类风湿性关节炎和脓毒性休克。可溶性TNF α通过膜锚定蛋白酶从其膜结合前体释放，最近被鉴定为称为TNF α转化酶或TACE的多结构域金属蛋白酶。我们已经将TACE的催化结构域与异羟肟酸抑制剂共结晶，并解析了其2.0埃晶体结构。该结构揭示了类似于蛇毒金属蛋白酶的多肽折叠和催化锌环境，将TACE鉴定为adamalysin/ADAM家族的成员。但是，许多大的插入环会生成唯一的曲面特征。pro-TNF α切割位点与TACE的活性位点相吻合，但似乎也由其相对于致密三聚体TNF α锥的基底的位置决定。TACE的活性位点裂缝与基质金属蛋白酶具有相同的性质，但表现出独特的特征，如深S3'口袋与表面下的S1'特异性口袋合并。因此，该结构为设计特异性合成TACE抑制剂开辟了不同的途径，该抑制剂可以在体内作为有效的治疗剂来调节TNF α诱导的病理生理学效应，并且还可能有助于控制相关的脱落过程。
Tumor necrosis factor-alpha (TNF alpha) 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 alpha is released from its membrane-hound precursor by a membrane-anchored proteinase, recently identified as a multidomain metalloproteinase called TNF alpha-converting enzyme or TACE. We have cocrystallized the catalytic domain of TACE with a hydroxamic acid inhibitor and have solved its 2.0 Angstrom 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 alpha 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 alpha 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 alpha-induced pathophysiological effects, and might also help to control related shedding processes.