1] School of Medicine and Medical Science, University College Dublin, Dublin, Ireland. [2].
Nat Chem Biol. 2013 Sep;9(9):540-7. doi: 10.1038/nchembio.1294. Epub 2013 Jul 14.
Hepatitis B virus (HBV) is an infectious, potentially lethal human pathogen. However, there are no effective therapies for chronic HBV infections. Antiviral development is hampered by the lack of high-resolution structures for essential HBV protein-protein interactions. The interaction between preS1, an HBV surface-protein domain, and its human binding partner, γ2-adaptin, subverts the membrane-trafficking apparatus to mediate virion export. This interaction is a putative drug target. We report here atomic-resolution descriptions of the binding thermodynamics and structural biology of the interaction between preS1 and the EAR domain of γ2-adaptin. NMR, protein engineering, X-ray crystallography and MS showed that preS1 contains multiple γ2-EAR-binding motifs that mimic the membrane-trafficking motifs (and binding modes) of host proteins. These motifs localize together to a relatively rigid, functionally important region of preS1, an intrinsically disordered protein. The preS1-γ2-EAR interaction was relatively weak and efficiently outcompeted by a synthetic peptide. Our data provide the structural road map for developing peptidomimetic antivirals targeting the γ2-EAR-preS1 interaction.
乙型肝炎病毒 (HBV) 是一种具有传染性、潜在致命性的人类病原体。然而，目前还没有针对慢性 HBV 感染的有效治疗方法。由于缺乏关键的 HBV 蛋白-蛋白相互作用的高分辨率结构，抗病毒药物的研发受到了阻碍。HBV 表面蛋白域 preS1 与其人类结合伴侣 γ2-衔接蛋白之间的相互作用破坏了膜运输装置，从而介导病毒粒子的输出。这种相互作用是一个潜在的药物靶点。我们在此报告了 preS1 与 γ2-衔接蛋白的 EAR 结构域之间相互作用的结合热力学和结构生物学的原子分辨率描述。NMR、蛋白质工程、X 射线晶体学和 MS 表明，preS1 包含多个模拟宿主蛋白的膜运输基序（和结合模式）的 γ2-EAR 结合基序。这些基序共同定位于 preS1 中一个相对刚性的、功能重要的区域，而 preS1 是一种固有无序的蛋白质。preS1-γ2-EAR 相互作用相对较弱，可被合成肽有效竞争。我们的数据为开发针对 γ2-EAR-preS1 相互作用的肽模拟抗病毒药物提供了结构蓝图。
