PDF(Pubmed)
Abstract：
The human myxovirus resistance B (MxB) protein is an interferon-induced restriction factor that fights a wide range of viruses. We previously demonstrated that MxB binds to hepatitis C virus (HCV)-encoded non-structural protein 5A (NS5A) and inhibits HCV infection by impairing the formation of cyclophilin A (CypA)-NS5A complex. However, the molecular details about how the presence of MxB diminishes the binding of NS5A to CypA remain uncovered. In this study, through molecular dynamic simulations and biochemical assays, we characterized that MxB binds to NS5A domain I through its N-terminal and GTPase domains. Specifically, amino acids (aa.) 189-191 and aa. 330-334 within MxB, together with NS5A residues aa. 71-73, are crucial for MxB-NS5A interaction. Furthermore, we predicted the CypA:NS5A and CypA:NS5A:MxB complexes and calculated the per-residue energy decomposition for identified key residues of the CypA-NS5A interface. A 28% decrease in CypA-NS5A binding affinity was observed in the presence of MxB, suggesting a weakened CypA-NS5A association upon binding of MxB to NS5A, which may contribute to the MxB-mediated inhibitory effect on the formation of CypA-NS5A complex. This work provides information for the antiviral mechanism of MxB and may facilitate the discovery of new strategies to combat CypA-dependent viruses.
摘要：
人粘液病毒抗性B（MxB）蛋白是干扰素诱导的限制因子，可抵抗多种病毒。我们先前证明MxB与丙型肝炎病毒（HCV）编码的非结构蛋白5A（NS5A）结合，并通过损害亲环蛋白A（CypA）-NS5A复合物的形成来抑制HCV感染。然而,关于MxB的存在如何减少NS5A与CypA结合的分子细节仍未发现。在这项研究中,通过分子动力学模拟和生化分析，我们表征了MxB通过其N末端和GTP酶结构域与NS5A结构域I结合。具体来说,氨基酸（aa.)189-191和AA。330-334在MxB内，连同NS5A残基aa。71-73对MxB-NS5A相互作用至关重要。此外，我们预测了CypA：NS5A和CypA：NS5A：MxB复合物，并计算了CypA-NS5A界面确定的关键残基的每个残基能量分解。在MxB的存在下，观察到CypA-NS5A结合亲和力降低了28％，表明在MxB与NS5A结合时CypA-NS5A结合减弱，这可能有助于MxB介导的对CypA-NS5A复合物形成的抑制作用。这项工作为MxB的抗病毒机制提供了信息，并可能有助于发现对抗CypA依赖性病毒的新策略。
