Crystal structure of human cytosolic phospholipase A2 reveals a novel topology and catalytic mechanism
Crystal structure of human cytosolic phospholipase A2 reveals a novel topology and catalytic mechanism
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DOI：
10.1016/s0092-8674(00)80744-8
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发表时间：
1999-04-30
期刊：
影响因子：
64.5
通讯作者：
Somers, WS
中科院分区：
文献类型：
--
作者：
Dessen, A;Tang, J;Somers, WS
胞浆磷脂酶A，启动生物合成的阿糖胞苷，白三烯，血小板活化因子（PAF），介质的病理生理哮喘和关节炎。在这里，我们报告了人cPLA（2）在2.5埃的X射线晶体结构。cPLA（2）由N端钙依赖性脂质结合/C2结构域和催化单元组成，其拓扑结构与其他脂肪酶不同。一个不寻常的Ser-Asp二分体位于一个深裂缝的中心，一个主要是疏水性的漏斗选择性地切割花生四烯酸磷脂。该结构揭示了一个灵活的盖子，必须移动，以允许底物进入活性位点，从而解释了这种重要的脂肪酶的界面活化。
Cytosolic phospholipase A, initiates the biosynthesis of prostaglandins, leukotrienes, and platelet-activating factor (PAF), mediators of the pathophysiology of asthma and arthritis. Here, we report the X-ray crystal structure of human cPLA(2) at 2.5 Angstrom. cPLA(2) consists of an N-terminal calcium-dependent lipid-binding/C2 domain and a catalytic unit whose topology is distinct from that of other lipases. An unusual Ser-Asp dyad located in a deep cleft at the center of a predominantly hydrophobic funnel selectively cleaves arachidonyl phospholipids. The structure reveals a flexible lid that must move to allow substrate access to the active site, thus explaining the interfacial activation of this important lipase.