Maynes Jason T, Luu Hue A, Cherney Maia M, Andersen Raymond J, Williams David, Holmes Charles F B, James Michael N G
Canadian Institutes of Health Research, Group in Protein Structure and Function Department of Biochemistry, Faculty of Medicine, University of Alberta, Edmonton, Alta, Canada T6G 2H7.
J Mol Biol. 2006 Feb 10;356(1):111-20. doi: 10.1016/j.jmb.2005.11.019. Epub 2005 Nov 22.
The microcystins and nodularins are tumour promoting hepatotoxins that are responsible for global adverse human health effects and wildlife fatalities in countries where drinking water supplies contain cyanobacteria. The toxins function by inhibiting broad specificity Ser/Thr protein phosphatases in the host cells, thereby disrupting signal transduction pathways. A previous crystal structure of a microcystin bound to the catalytic subunit of protein phosphatase-1 (PP-1c) showed distinct changes in the active site region when compared with protein phosphatase-1 structures bound to other toxins. We have elucidated the crystal structures of the cyanotoxins, motuporin (nodularin-V) and dihydromicrocystin-LA bound to human protein phosphatase-1c (gamma isoform). The atomic structures of these complexes reveal the structural basis for inhibition of protein phosphatases by these toxins. Comparisons of the structures of the cyanobacterial toxin:phosphatase complexes explain the biochemical mechanism by which microcystins but not nodularins permanently modify their protein phosphatase targets by covalent addition to an active site cysteine residue.
微囊藻毒素和节球藻毒素是具有促癌作用的肝毒素，在饮用水源含有蓝藻的国家，它们会对人类健康产生全球范围的不良影响，并导致野生动物死亡。这些毒素通过抑制宿主细胞中具有广泛特异性的丝氨酸/苏氨酸蛋白磷酸酶发挥作用，从而扰乱信号转导通路。与结合了其他毒素的蛋白磷酸酶-1（PP-1c）结构相比，先前微囊藻毒素与蛋白磷酸酶-1催化亚基结合的晶体结构显示，活性位点区域有明显变化。我们解析了蓝藻毒素莫毒菌素（节球藻毒素-V）和二氢微囊藻毒素-LA与人蛋白磷酸酶-1c（γ同工型）结合的晶体结构。这些复合物的原子结构揭示了这些毒素抑制蛋白磷酸酶的结构基础。对蓝藻毒素与磷酸酶复合物结构的比较，解释了微囊藻毒素而非节球藻毒素通过共价结合到活性位点半胱氨酸残基上而永久性修饰其蛋白磷酸酶靶点的生化机制。
