VIRAL MEMBRANE AND GLYCOPROTEIN STRUCTURE

甲型流感病毒血凝素（HA）糖蛋白 介导细胞受体结合和膜融合， 病毒核衣壳进入细胞质的影响 开发这一结果对于理解病毒 感染和一般重要性，以了解蛋白质配体 相互作用、抑制剂设计和膜融合。膜融合是一种 对许多病毒的基本细胞过程知之甚少， 感染（包括HIV-1）和许多生物现象， 胞内小泡运输，突触传递，受精， 和肌肉发育。 建议的受体结合研究包括晶体学分析 受体特异性，通过诱变分析结合能，和 高亲和力配体的设计。后者基于找到第二个 结合位点，并通过结合策略增加亲和力 在前一个时期发现的。拟议的膜研究 融合寻求确定低pH融合活性的关系 溶液中HA的构象与最近测定的可溶性， 结晶低pH HA片段。诱变、半合成和NMR 实验被提出来研究被认为是 融合活动期间的紊乱。 1957年甲型流感病毒株HA和HEF的X射线研究 C型流感病毒的血凝素-酯酶-膜蛋白 建议界定其职能的结构基础，并提供一个 设计实验的框架， 膜融合活性。 关于流感病毒膜离子通道M2的结构信息， 并且其与抗病毒抑制剂金刚烷胺的相互作用将 通过晶体学、NMR和对合成跨膜的研究， 碎片

Mechanisms of how the influenza A virus hemoagglutinin (HA) glycoprotein mediates both cellular-receptor binding and the membrane fusion that effects entry of viral nucleocapsids into the cytoplasm are being developed. The results are of specific importance to understanding viral infections and of general importance to understanding protein-ligand interactions, inhibitor design, and membrane fusion. Membrane fusion is a poorly understood but fundamental cellular process critical to many viral infections (including HIV-1) and numerous biological phenomena including intracellular vesicle trafficking, synaptic transmission, fertilization, and muscle development. Proposed studies on receptor binding include crystallographic analysis of receptor specificity, analysis of binding energetics by mutagenesis, and the design of high affinity ligands. The latter based on finding a second binding site and by combining strategies for increasing affinity discovered in the previous grant period. Proposed studies on membrane fusion seek to determine the relationship of the low pH fusion active conformation of HA in solution to that recently determined for a soluble, crystalline low pH HA fragment. Mutagenesis, semi-synthesis, and NMR experiments are proposed to study parts of the structure thought to disorder during fusion activity. X-ray studies on HA from a 1957 pandemic influenza A strain and the HEF (Hemoagglutinin-esterase-membrane) protein of influenza C virus are proposed to define structural bases for their functions and to provide a framework for designing experiments on puzzling differences in their membrane fusion activities. Structural information about M2, an influenza virus membrane ion channel, and its interaction with the anti-viral inhibitor amantadine will be sought by crystallography, NMR, and studies on a synthetic transmembrane fragment.