Structural basis for the activation of anthrax adenylyl cyclase exotoxin by calmodulin
Structural basis for the activation of anthrax adenylyl cyclase exotoxin by calmodulin
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DOI：
10.1038/415396a
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发表时间：
2002-01-24
期刊：
影响因子：
64.8
通讯作者：
Tang, WJ
中科院分区：
文献类型：
--
作者：
Drum, CL;Yan, SZ;Tang, WJ
水肿因子是一种钙调素激活的腺苷酸环化酶，在炭疽的发病机制中起重要作用。在这里，我们报告有和没有结合钙调素的水肿因子的x线结构。水肿因子与哺乳动物腺苷酸环化酶或其他蛋白质没有明显的结构同源性。在活性位点上，39-脱氧atp和一个金属离子以组氨酸351为催化碱进行催化。这种机制不同于哺乳动物腺苷酸环化酶的双金属离子催化机制。水肿因子的四个离散区域形成一个表面，可以识别钙调蛋白的延伸构象，这与钙调蛋白与效应肽结合的其他结构中观察到的塌陷构象非常不同。在钙调素结合中，相对分子质量为15,000的水肿因子螺旋结构域经历了15埃的平移和远离水肿因子催化核心的30度旋转，从而稳定了无序环并导致酶激活。这些变构变化提供了钙调素如何调节其靶标之一的第一个分子细节。
Oedema factor, a calmodulin-activated adenylyl cyclase, is important in the pathogenesis of anthrax. Here we report the X-ray structures of oedema factor with and without bound calmodulin. Oedema factor shares no significant structural homology with mammalian adenylyl cyclases or other proteins. In the active site, 39-deoxy-ATP and a single metal ion are well positioned for catalysis with histidine 351 as the catalytic base. This mechanism differs from the mechanism of two-metal-ion catalysis proposed for mammalian adenylyl cyclases. Four discrete regions of oedema factor form a surface that recognizes an extended conformation of calmodulin, which is very different from the collapsed conformation observed in other structures of calmodulin bound to effector peptides. On calmodulin binding, an oedema factor helical domain of relative molecular mass 15,000 undergoes a 15 Angstrom translation and a 30degrees rotation away from the oedema factor catalytic core, which stabilizes a disordered loop and leads to enzyme activation. These allosteric changes provide the first molecular details of how calmodulin modulates one of its targets.