Insight into the Molecular Mechanism for the Discrepant Inhibition of Microcystins (MCLR, LA, LF, LW, LY) on Protein Phosphatase 2A.
Insight into the Molecular Mechanism for the Discrepant Inhibition of Microcystins (MCLR, LA, LF, LW, LY) on Protein Phosphatase 2A.
复制标题
深入了解微囊藻毒素（MCLR、LA、LF、LW、LY）对蛋白磷酸酶 2A 差异抑制的分子机制
作者：
微囊藻毒素（MCs）由于结构上的差异，对蛋白磷酸酶（PPs）表现出不同程度的抑制作用。为了充分评估不同抑制作用的潜在机制，我们选择了Z4位置残基不同的5种最常见的MCs作为测试毒素。检测其对PP2A的抑制顺序为：MCLR > MCLW > MCLA > MCLF > MCLY。结合同源性建模和分子对接技术，得到了MCs与PP2A的主要相互作用参数。主要相互作用参数与抑制效果的相关分析表明，Z4的疏水性对MCs与PP2A的相互作用有重要影响。疏水性Z4的引入直接削弱了氢键Z4→Pro213和Z4←Arg214，间接削弱了氢键Adda5←Asn117、Glu6←Arg89和MeAsp3←Arg89，间接增强了离子键Glu6←Arg89、Glu6- mn12 +和Glu6- mn22 +。这样就阻断了MCs与PP2A的结合，从而进一步影响了PP2A与催化中心的Mn2+离子的相互作用；金属键Asp85-Mn12+和Asp85-Mn22+减弱，金属键His241-Mn12+增强。因此，催化中心的相互作用受到不同程度的抑制，从而降低了MCs的毒性。
Microcystins (MCs) exhibit diversified inhibition effects on protein phosphatases (PPs) due to their structural differences. To fully evaluate the potential mechanism for the discrepant inhibition effects, the five most frequent MCs with varying residues at position Z4 were selected as the tested toxins. Their inhibition sequence on PP2A was detected as follows: MCLR > MCLW > MCLA > MCLF > MCLY. Combined with homology modeling and molecular docking technology, the major interaction parameters between the MCs and PP2A were obtained. The correlation analysis for the major interaction parameters and inhibition effects showed that the hydrophobicity of Z4 had an important influence on the interaction of the MCs to PP2A. The introduction of hydrophobic Z4 directly weakened hydrogen bonds Z4→Pro213 and Z4←Arg214, indirectly weakened hydrogen bonds Adda5←Asn117, Glu6←Arg89, and MeAsp3←Arg89, but indirectly enhanced ionic bonds Glu6←Arg89, Glu6-Mn12+, and Glu6-Mn22+. In this way, the combination of the MCs with PP2A was blocked, and thus, the interactions between PP2A and the Mn2+ ions (in the catalytic center) were further affected; metal bonds Asp85-Mn12+ and Asp85-Mn22+ were weakened, while metal bond His241-Mn12+ was enhanced. As a result, the interactions in the catalytic center were inhibited to varying degrees, resulting in the reduced toxicity of MCs.
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影响因子：
7.3
作者：
Nasa I;Rusin SF;Kettenbach AN;Moorhead GB
通讯作者：
Moorhead GB
DOI：
10.1007/s12576-017-0556-6
发表时间：
2018-01
期刊：
The journal of physiological sciences : JPS
影响因子：
--
作者：
Takai A;Eto M;Hirano K;Takeya K;Wakimoto T;Watanabe M
通讯作者：
Watanabe M
影响因子：
15.1
作者：
Zong, Wansong;Sun, Feng;Pei, Ruoting
通讯作者：
Pei, Ruoting
影响因子：
11.4
作者：
Pestana, Carlos J.;Moura, Diana S.;Lawton, Linda A.
通讯作者：
Lawton, Linda A.
影响因子：
2.8
作者：
Sedan, Daniela;Andrinolo, Dario;Marra, Carlos A.
通讯作者：
Marra, Carlos A.