Structural and mechanistic studies of herpesvirus entry into host cells

疱疹病毒是人类病原体，终身感染宿主，引起唇疱疹， 生殖器疱疹、失明、脑炎、癌症和危及生命的疾病， 免疫力低下的人。我的研究目标是了解原子- 详细说明疱疹病毒如何进入宿主细胞。这些信息将是非常宝贵的， 设计抗疱疹病毒疗法，以对抗病毒感染和细胞-细胞 传播. 疱疹病毒进入细胞的机制非常复杂。而另一个被包裹着的 病毒使用单一蛋白质来影响细胞进入，所有疱疹病毒都需要至少三种蛋白质。 蛋白质：gB、gH和gL。这三种蛋白质被认为完成了 病毒和细胞膜-病毒进入的关键步骤-但它们的确切功能是 晦涩难懂。我的目标是确定单纯疱疹病毒的gB和gH/gL蛋白 (HSV)共同完成膜融合，以及来自细胞膜的信号如何 受体结合蛋白gD触发膜融合机制。如何发现 这些蛋白质在HSV感染中起作用，也将揭示它们在其他疾病中的功能。 疱疹病毒，因为膜融合机制，即，gB、gH和gL， 保守的我的方法将联合收割机结合X射线晶体学的力量来确定 单个蛋白质的结构与其他生物物理和生物化学的严格性 技术来研究它们的相互作用。这项研究的结果将是一个彻底的 疱疹病毒介导的病毒融合的确定和精细的详细图片， 和细胞膜。 以前在单组分系统中对病毒介导的膜融合的研究， 为膜融合的一般机制提供了许多重要的见解， 参与许多正常的细胞过程。但是复杂的多蛋白融合 疱疹病毒的机制是一个更好的模型，调节，多组分细胞 膜融合因此，如果我们确定疱疹病毒糖蛋白如何相互作用， 在细胞进入过程中驱动膜融合，我们将从根本上推进我们的机制， 了解膜融合。

Herpesviruses are human pathogens that infect their hosts for life, causing cold sores, genital herpes, blindness, encephalitis, cancers, and life-threatening conditions in immuno-compromised individuals. The goal of my research is to understand in atomic- level detail how herpesviruses enter host cells. Such information will be invaluable in designing anti-herpesvirus therapeutics to combat both viral infections and cell-cell spread. The herpesvirus cell-entry mechanism is very complex. Whereas other enveloped viruses use a single protein to effect cell entry, all herpesviruses require at least three proteins: gB, gH, and gL. These three proteins are thought to accomplish the fusion of viral and cell membranes – a pivotal step in viral entry – but their exact functions are obscure. I aim to determine how the gB and gH/gL proteins of Herpes Simplex Virus (HSV) work together to accomplish membrane fusion and how the signal from the receptor-binding protein, gD, triggers the membrane-fusion machinery. Uncovering how these proteins work in HSV infection will also reveal their functions in other herpesviruses because the membrane-fusion machinery, i.e., gB, gH, and gL, is highly conserved. My approach will combine the power of x-ray crystallography to determine the structures of individual proteins with the rigor of other biophysical and biochemical techniques to study their interactions. The outcome of this research will be a thoroughly determined and finely detailed picture of the herpesvirus-mediated fusion of the viral and cell membranes. Previous studies of virus-mediated membrane fusion in single-component systems have provided many crucial insights into the general mechanism of membrane fusion, involved in many normal cellular processes. But the complex multiprotein fusion machinery of herpesviruses is a better model for the regulated, multi-component cellular membrane fusion. Therefore, if we establish how herpesvirus glycoproteins interact to drive membrane fusion during cell entry, we will advance fundamentally our mechanistic understanding of membrane fusion.