Structural basis for selective inhibition of cyclooxygenase-2 by anti-inflammatory agents
Structural basis for selective inhibition of cyclooxygenase-2 by anti-inflammatory agents
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DOI：
10.1038/384644a0
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发表时间：
1996-12-19
期刊：
影响因子：
64.8
通讯作者：
Stallings, WC
中科院分区：
文献类型：
--
作者：
Kurumbail, RG;Stevens, AM;Stallings, WC
前列腺素类和糖皮质激素类是有效的炎症介质。非甾体抗炎药（NSAID）通过抑制前列腺素的产生发挥作用。NSAID的药理学靶点是环氧合酶（考克斯，也称为PGH合酶），其催化花生四烯酸代谢的第一个关键步骤（1，2）。已知膜蛋白考克斯的两种同种型（3）：考克斯-1，其在大多数组织中组成型表达，负责异甘草素的生理产生（4）;和考克斯-2，其由炎性细胞中的细胞因子、有丝分裂原和内毒素诱导（5），负责炎症期间异甘草素的升高产生（6，7）。羊考克斯-1与几种NSAID复合的结构已被确定（8-10）。在这里，我们报告的结构，unliganded鼠考克斯-2和复合物与氟比洛芬，吲哚美辛和SC-558，选择性考克斯-2抑制剂，确定在3.0至25埃分辨率。这些结构解释了选择性抑制考克斯-2的结构基础，并证明了与时间依赖性抑制相关的一些构象变化。
PROSTAGLANDINS and glucocorticoids are potent mediators of inflammation. Non-steroidal anti-inflammatory drugs (NSAIDs) exert their effects by inhibition of prostaglandin production. The pharmacological target of NSAIDs is cyclooxygenase (COX, also known as PGH synthase), which catalyses the first committed step in arachidonic-acid metabolism(1,2). Two isoforms of the membrane protein COX are known(3): COX-1, which is constitutively expressed in most tissues, is responsible for the physiological production of prostaglandins(4); and COX-2, which is induced by cytokines, mitogens and endotoxins in inflammatory cells(5), is responsible for the elevated production of prostaglandins during inflammation(6,7). The structure of ovine COX-1 complexed with several NSAIDs has been determined(8-10). Here we report the structures of unliganded murine COX-2 and complexes with flurbiprofen, indomethacin and SC-558, a selective COX-2 inhibitor, determined at 3.0 to 25 Angstrom resolution. These structures explain the structural basis for the selective inhibition of COX-2, and demonstrate some of the conformational changes associated with time-dependent inhibition.