The productive conformation of arachidonic acid bound to prostaglandin synthase
The productive conformation of arachidonic acid bound to prostaglandin synthase
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DOI：
10.1126/science.289.5486.1933
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发表时间：
2000-09-15
期刊：
影响因子：
56.9
通讯作者：
Garavito, RM
中科院分区：
文献类型：
--
作者：
Malkowski, MG;Ginell, SL;Garavito, RM
前列腺素 H 合酶-1 和 -2（PGHS-1 和 -2）催化前列腺素合成的关键步骤，是阿司匹林等非甾体抗炎药 (NSAID) 的靶标。我们以 3 埃的分辨率确定了 PGHS-1 的结构，其中花生四烯酸 (AA) 结合在化学生产构象中。该脂肪酸采用延伸的 L 形构象，定位 AA 的 13proS 氢，以便被可能的自由基供体 tyrosine-385 提取。碳的11位(C-11)的反面还存在用于添加氧的空间。虽然这种构象允许在 C-11 和 C-9 之间形成内过氧化物，但这也意味着必须发生随后的构象重排，以允许形成 C-8/C-12 键并定位 C-15 以接受第二个氧分子的攻击。
Prostaglandin H synthase-1 and -2 (PGHS-1 and -2) catalyze the committed step in prostaglandin synthesis and are targets for nonsteroidal anti-inflammatory drugs (NSAIDs) Like aspirin. We have determined the structure of PGHS-1 at 3 angstrom resolution with arachidonic acid (AA) bound in a chemically productive conformation. The fatty acid adopts an extended L-shaped conformation that positions the 13proS hydrogen of AA for abstraction by tyrosine-385, the Likely radical donor. A space also exists for oxygen addition on the antarafacial surface of the carbon in the 11-position (C-11). While this conformation allows endoperoxide formation between C-11 and C-9, it also implies that a subsequent conformational rearrangement must occur to allow formation of the C-8/C-12 bond and to position C-15 for attack by a second molecule of oxygen.