Elucidating the mechanisms of accelerated dissociation and allosteric processes in the antibody immunoglobulin E

阐明抗体免疫球蛋白 E 加速解离和变构过程的机制

• 批准号: BB/P000436/1
• 负责人: James McDonnell
• 金额: $ 37.28万
• 依托单位: King's College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FP000436%2F1
• 关键词: Elucidating; mechanisms; accelerated; dissociation; allosteric

The incidence of allergic disease has increased alarmingly in recent decades, nowhere more so than in the UK, where rates are now among the highest in the world. These conditions range from mild hayfever to life-threatening severe asthma or anaphylaxis, and include allergic rhinitis, atopic dermatitis and food allergies. All of these conditions involve reactions to otherwise innocuous substances in the environment, and all involve a particular type of antibody known as IgE. We have studied this antibody over many years, and understand much about how it differs from other types of antibody such as the protective IgG antibodies. All antibodies play two important roles: they recognize and bind - usually, in the case of IgG - to foreign invaders such as bacteria or viruses using one part of the antibody molecule, and then bind via another part to "receptor" molecules on cells that become activated to destroy the foreign material. But IgE has the remarkable property of binding so tightly to the cells that once bound it almost never comes off within the lifetime of the cell. This means that when an allergen such as pollen, or peanut, or house dust mite, gets into the body (through airway, gut or skin) and binds to the IgE antibodies, they can activate the cells immediately to deliver a powerful, inflammatory response. The cells are effectively "sensitized" to react to the allergen.IgE can be targeted to alleviate allergic conditions, and an "anti-IgE" antibody therapy, called omalizumab (XolairTM), may be prescribed for certain patients with severe asthma. It works by binding to IgE molecules and blocking them from binding to the cell receptors, thus preventing sensitization; however, IgE already receptor-bound, the "pathogenic" IgE, is unaffected. It now appears that Xolair at extremely high levels, well above those reached therapeutically, can actually bind to receptor-bound IgE and actively remove it. This is a remarkable discovery, and one that would have profound implications for anti-allergy therapy if it could be understood and harnessed. We believe that the key to understanding this phenomenon lies in the unique flexibility of the IgE antibody. Our previous studies have revealed, quite unexpectedly, that the receptor-binding part of the IgE molecule can adopt several different shapes, and indeed can communicate signals from one part of the molecule to another through subtle changes in shape. This phenomenon - called allostery ("other shape") - is what we want to explore in detail using a technique that can probe these changes and this communication at the atomic level. If we can understand how binding to one part of the IgE molecule (which is accessible when IgE is bound on the cell) can release it at another site (where it binds to the receptor), then we can begin to develop a much more effective therapeutic agent for allergic disease. However, the benefits may go well beyond allergic disease. The molecular processes of health and disease ubiquitously involve interactions between different proteins, and many of these interactions, like the IgE/receptor interaction, are very tight. Targeting these protein/protein interactions is traditionally considered to be difficult, but an understanding of allostery could open up new possibilities for intervening in a range of diverse medical conditions.We are collaborating in this project with the pharmaceutical company UCB with whom we have been working for several years. They are providing protein materials for the analysis, and their interest in understanding the IgE/receptor system, publishing the results, and applying this knowledge to other protein/protein interactions will ensure the rapid dissemination and commercial translation of the results of this study.

近几十年来，过敏性疾病的发病率以惊人的速度增长，其中英国的发病率最高，现在是世界上最高的。这些疾病的范围从轻微的花粉热到危及生命的严重哮喘或过敏反应，包括过敏性鼻炎，特应性皮炎和食物过敏。所有这些情况都涉及对环境中其他无害物质的反应，并且都涉及称为IgE的特定类型的抗体。我们已经研究这种抗体多年，并了解它与其他类型的抗体（如保护性IgG抗体）的不同之处。所有的抗体都扮演着两个重要的角色：它们识别并结合--通常是IgG --使用抗体分子的一部分与细菌或病毒等外来入侵者结合，然后通过另一部分与细胞上的“受体”分子结合，这些分子被激活以摧毁外来物质。但IgE具有与细胞紧密结合的显著特性，一旦结合，在细胞的生命周期内几乎不会脱落。这意味着，当过敏原如花粉、花生或屋尘螨进入人体（通过气道、肠道或皮肤）并与IgE抗体结合时，它们可以立即激活细胞，产生强大的炎症反应。这些细胞被有效地“致敏”以对过敏原做出反应。IgE可以被靶向以减轻过敏状况，并且“抗IgE”抗体疗法，称为奥马珠单抗（XolairTM），可以被开给某些患有严重哮喘的患者。它通过与IgE分子结合并阻止它们与细胞受体结合而起作用，从而防止致敏;然而，已经与受体结合的IgE，即“致病性”IgE，不受影响。现在看来，极高水平的Xolair（远高于治疗水平）实际上可以与受体结合的IgE结合并主动清除它。这是一个了不起的发现，如果能够理解和利用它，将对抗过敏治疗产生深远的影响。我们认为，理解这种现象的关键在于IgE抗体的独特灵活性。我们之前的研究已经非常出乎意料地发现，IgE分子的受体结合部分可以采用几种不同的形状，并且确实可以通过形状的细微变化将信号从分子的一部分传递到另一部分。这种现象-称为变构（“其他形状”）-是我们想要详细探索的，使用一种可以在原子水平上探测这些变化和这种通信的技术。如果我们能够理解与IgE分子的一部分结合（当IgE结合在细胞上时可以接近）如何在另一个位点（它与受体结合的地方）释放它，那么我们就可以开始开发一种更有效的治疗过敏性疾病的药物。然而，其益处可能远远超出过敏性疾病。健康和疾病的分子过程普遍涉及不同蛋白质之间的相互作用，其中许多相互作用，如IgE/受体相互作用，非常紧密。针对这些蛋白质/蛋白质相互作用传统上被认为是困难的，但对变构的理解可以为干预一系列不同的医疗条件开辟新的可能性。我们正在与制药公司UCB合作这个项目，我们已经与他们合作了几年。他们为分析提供蛋白质材料，他们对了解IgE/受体系统、发表结果并将这些知识应用于其他蛋白质/蛋白质相互作用的兴趣将确保本研究结果的快速传播和商业翻译。