Thunnissen M M, Ab E, Kalk K H, Drenth J, Dijkstra B W, Kuipers O P, Dijkman R, de Haas G H, Verheij H M
Laboratory of Chemical Physics, University of Groningen, The Netherlands.
Nature. 1990 Oct 18;347(6294):689-91. doi: 10.1038/347689a0.
Phospholipases A2 play a part in a number of physiologically important cellular processes such as inflammation, blood platelet aggregation and acute hypersensitivity. These processes are all initiated by the release of arachidonic acid from cell membranes which is catalysed by intracellular phospholipases A2 and followed by conversion of arachidonic acid to prostaglandins, leukotrienes or thromboxanes. An imbalance in the production of these compounds can lead to chronic inflammatory diseases such as rheumatoid arthritis and asthma. Inhibitors of phospholipase A2 might therefore act to reduce the effects of inflammation, so structural information about the binding of phospholipase A2 to its substrates could be helpful in the design of therapeutic drugs. The three-dimensional structure is not known for any intracellular phospholipase A2, but these enzymes share significant sequence homology with secreted phospholipases, for which some of the structures have been determined. Here we report the structure of a complex between an extracellular phospholipase A2 and a competitively inhibiting substrate analogue, which reveals considerable detail about the interaction and suggests a mechanism for catalysis by this enzyme.
磷脂酶A2在许多重要的生理细胞过程中发挥作用，如炎症、血小板聚集和急性超敏反应。这些过程均由细胞膜中花生四烯酸的释放引发，这一过程由细胞内磷脂酶A2催化，随后花生四烯酸转化为前列腺素、白三烯或血栓素。这些化合物生成的失衡会导致慢性炎症性疾病，如类风湿性关节炎和哮喘。因此，磷脂酶A2抑制剂可能会起到减轻炎症的作用，所以关于磷脂酶A2与其底物结合的结构信息可能有助于治疗药物的设计。目前还不清楚任何细胞内磷脂酶A2的三维结构，但这些酶与已确定了一些结构的分泌型磷脂酶具有显著的序列同源性。在此，我们报道了一种细胞外磷脂酶A2与一种竞争性抑制底物类似物之间的复合物结构，该结构揭示了两者相互作用的大量细节，并提出了这种酶的催化机制。
