A molecular basis for different interactions of marine toxins with protein phosphatase-1 - Molecular models for bound motuporin, microcystins, okadaic acid, and calyculin A
A molecular basis for different interactions of marine toxins with protein phosphatase-1 - Molecular models for bound motuporin, microcystins, okadaic acid, and calyculin A
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DOI：
10.1074/jbc.272.8.5087
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发表时间：
1997-02-21
影响因子：
4.8
通讯作者：
Holmes, CFB
中科院分区：
文献类型：
--
作者：
Bagu, JR;Sykes, BD;Holmes, CFB
具有肝毒性的环状七肽微囊藻毒素和环状五肽结节藻毒素是强大的肝脏肿瘤促进剂和蛋白磷酸酶-1和-2A（PP-1c和PP-2Ac）催化亚单位的有效抑制剂。与与PP-1和PP-2A共价相互作用的微囊藻毒素形成鲜明对比，结节藻毒素不与PP-1和PP-2A共价结合并且还可能具有独特的致癌特性。微囊藻毒素-LR 的构象已在溶液中测定并与 PP lc 结合。我们在此表明，两种不同的微囊藻毒素结构同系物（微囊藻毒素-LR 和-LL）的游离核磁共振溶液结构与微囊藻毒素-LR 的结合晶体结构非常相似。我们利用这一发现，通过使用 Metropolis Monte Carlo 模型将微囊藻毒素-LL 和海洋毒素莫图孔蛋白（节球蛋白-V）的溶液结构对接到 PP-1c 的晶体结构上。当与 PP-1c 结合时，这两种毒素占据与微囊藻毒素-LR 相似的位置。然而，尽管与微囊藻毒素-LR 相比，微囊藻毒素-LL 的结构方向存在相对较小的差异，但 motuporin 中 N-甲基脱氢丁氨酸残基的位置相对于微囊藻毒素-LR 中类似的 N-甲基脱氢丙氨酸残基的位置存在显着差异。我们认为这种方向上的差异为为什么结节菌素不能与 PP-1c 形成共价键提供了分子解释。此外，莫图孔蛋白中 N-甲基脱氢丁酸的预测位置位于 PP-1c-毒素复合物的表面，这可能因此促进与可能与其致癌特性有关的其他大分子的化学相互作用，PP-1c 和 PP-2Ac 也是其他海洋毒素（如冈田酸和花萼蛋白 A）的目标。因此，使用 Metropolis Monte Carlo 模型对接已知的冈田酸游离晶体结构是有意义的。这些实验预测，冈田酸和花萼蛋白 A 在三级结构和相对 PP-1c 结合位置方面与微囊藻毒素和莫图孔蛋白惊人地相似。
The hepatotoxic cyclic heptapeptide microcystins and cyclic pentapeptide nodularins are powerful liver tumor promoters and potent inhibitors of the catalytic sub units of protein phosphatase-1 and -2A (PP-1c and PP-2Ac), In marked contrast to microcystins, which interact covalently with PP-1 and PP-2A, the nodularins do not bind covalently to PP-1 and PP-2A and may additionally possess unique carcinogenic properties, The conformation of microcystin-LR has been determined in solution and bound to PP lc. We show here that the free NMR solution structures of two distinct microcystin structural congeners (microcystin-LR and -LL) are remarkably similar to the bound crystal structure of microcystin-LR, We have exploited this finding by using Metropolis Monte Carlo modeling to dock the solution structures of microcystin-LL and the marine toxin motuporin (nodularin-V) onto the crystal structure of PP-1c. Both of these toxins occupy a position similar to that of microcystin-LR when bound to PP-1c, However, al though there are relatively minor differences in the structural orientation of microcystin-LL compared with microcystin-LR, there is a striking difference in the position of the N-methyldehydrobutyrine residue in motuporin relative to the comparable N-methyldehydroalanine residue in microcystin-LR. We propose that this difference in orientation provides a molecular explanation for why nodularins are incapable of forming a covalent linkage with PP-1c. Furthermore, the predicted position of N-methyldehydrobutyrine in motuporin is at the surface of the PP-1c-toxin complex, which may thus facilitate chemical interaction with a further macromolecule(s) possibly relating to its carcinogenic properties, PP-1c and PP-2Ac are also targets for other marine toxins such as okadaic acid and calyculin A. It was therefore of interest to use Metropolis Monte Carlo modeling to dock the known free crystal structures of okadaic acid and calyculin A to the crystal structure of PP-1c, These experiments predict that both okadaic acid and calyculin A are strikingly similar to microcystins and motuporin in their tertiary structure and relative PP-1c binding position.