SMOCs: Novel Signal Transduction Complexes as New Targets for Drug Discovery

 描述（由申请人提供）：形成位置特异性的高阶信号复合物，现在称为超分子组织中心（SMOC），是先天免疫信号传导的几乎普遍特征。SMOC介导的信号转导不同于经典的信号转导，在经典的信号转导中，配体诱导的构象变化、酶激活和第二信使产生的连锁反应导致信号传递和放大。SMOC说明了涉及协同性，信号放大， 反应的阈值行为和时间延迟，以及邻近驱动的变构酶激活，激活和终止的空间和时间控制，以及生物活性的减少。 噪声这些关键的信号概念处于现代信号转导理论的最前沿，在严格的分子，结构和细胞生物学水平上理解它们将改变我们在基础和应用水平上处理先天免疫的方式。在这个先锋应用中，我们将研究这些概念的一个子集，这些概念直接指导有吸引力的新模型的开发，用于靶向药物发现，使用新的想法和方法。先天免疫对于宿主防御和炎症至关重要，并且其失调是许多人类疾病的基础，包括遗传性疾病、痛风、牛皮癣、狼疮、多发性硬化症、神经退行性疾病、糖尿病、溃疡性结肠炎和克罗恩病，仅举几例。我们建议，SMOCs提供了一个以前未开发的可药用蛋白质组，因为它们提供了机会，占主导地位的负面，而不是竞争性抑制作为其组装的协同性的结果。这些靶位点可能包括寡聚化结构域上的聚合界面、SMOC诱导的变构酶活化所需的固有弱相互作用以及细胞中SMOC形成所需的潜在SMOC-细胞骨架相互作用。从这些研究中学到的原则

 DESCRIPTION (provided by applicant): Formation of location-specific, higher-order signaling complexes, now called supramolecular organizing centers (SMOCs), is an almost universal feature of innate immune signaling. SMOC-mediated signal transduction is distinct from classical signal transduction, in which a chain reaction of ligand-induced conformational changes, enzyme activation and second messenger production leads to signal transmission and amplification. SMOCs illustrate important principles involving cooperativity, signal amplification, threshold behavior and time delay of response, as well as proximity-driven allosteric enzyme activation, spatial and temporal control of activation and termination, and reduction of biological noise. These key signaling concepts are at the forefront of modern signal transduction theory, and understanding them at a rigorous molecular, structural and cell biological level would transform how we approach innate immunity, at both basic and applied levels. In this Pioneer Application, we will investigate a subset of these concepts that directly guide the development of attractive new models for targeted drug discovery, using fresh ideas and methodologies. Innate immunity is critically important for host-defense and inflammation, and its dysregulation underlies many human diseases, including genetic disorders, gout, psoriasis, lupus, multiple sclerosis, neurodegenerative diseases, diabetes, ulcerative colitis and Crohn's disease, just to name a few. We propose that SMOCs provide a previously untapped druggable proteome as they offer opportunities for dominant negative, rather than competitive inhibition as a result of the cooperativity in their assembly. These target sites may include polymerization interfaces on the oligomerization domains, SMOC-induced, intrinsically weak interactions required for allosteric enzyme activation, and potential SMOC-cytoskeleton interactions required for SMOC formation in cells. The principles learned from these stud