Insight into the Molecular Mechanism for the Discrepant Inhibition of Microcystins (MCLR, LA, LF, LW, LY) on Protein Phosphatase 2A

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 Z(4) 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 Z(4) had an important influence on the interaction of the MCs to PP2A. The introduction of hydrophobic Z(4) directly weakened hydrogen bonds Z(4)→Pro(213) and Z(4)←Arg(214), indirectly weakened hydrogen bonds Adda(5)←Asn(117), Glu(6)←Arg(89), and MeAsp(3)←Arg(89), but indirectly enhanced ionic bonds Glu(6)←Arg(89), Glu(6)-Mn(1)(2+), and Glu(6)-Mn(2)(2+). In this way, the combination of the MCs with PP2A was blocked, and thus, the interactions between PP2A and the Mn(2+) ions (in the catalytic center) were further affected; metal bonds Asp(85)-Mn(1)(2+) and Asp(85)-Mn(2)(2+) were weakened, while metal bond His(241)-Mn(1)(2+) was enhanced. As a result, the interactions in the catalytic center were inhibited to varying degrees, resulting in the reduced toxicity of MCs.