Biomolecular Recognition and Binding Mechanisms

生物分子识别和结合机制

• 批准号: 9153571
• 负责人: Ruth Nussinov
• 金额: $ 43.97万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9153571
• 关键词: Accounting; Adverse drug effect; Adverse effects; Affect; Attention; Awareness; Behavior; Binding; Binding Sites; Bypass; Capsid; Cell Surface Receptors; Cell physiology; Cells; Communication; Complement; Complex; Comprehension; Cytotoxic Chemotherapy; DNA; Data; Deubiquitination; Development; Disease; Drug Design; Drug Targeting; Drug resistance; Electrostatics; Elements; Environment; Enzymes; Epidermal Growth Factor Receptor; Equilibrium; Equus caballus; Event; Family; Feedback; Future; Genome; Goals; Guidelines; Heart; Hydrogen Bonding; Immune response; Individual; Inflammation; Innovative Therapy; Knowledge; Length; Lesion; Life; Light; Malignant Neoplasms; Maps; Mediating; Membrane; Modeling; Modeling of Cellular Pathways; Molecular; Molecular Conformation; Molecular Machines; Molecular Motors; Mono-S; Mutation; NF-kappa B; Neoplasm Metastasis; Normal Cell; Oncogenes; Oncogenic; Organism; Outcome; Pathway interactions; Pharmaceutical Preparations; Pharmacology; Phase; Phosphotransferases; Physiological; Play; Positioning Attribute; Process; Protein Kinase; Proteins; RNA; Reaction; Regulation; Resolution; Rewards; Role; Sampling Biases; Shapes; Signal Pathway; Signal Transduction; Site; Somatic Mutation; Stress; Structure; Sum; Symptoms; System; Systems Biology; Therapeutic; To specify; Toll-Like Receptor Pathway; Toll-like receptors; Transport Reaction; Ubiquitin; Ubiquitin Like Proteins; Ubiquitination; Viral; Work; base; cancer cell; cancer therapy; data modeling; database structure; drug discovery; drug relapse; flexibility; functional genomics; improved; inhibitor/antagonist; killings; kinase inhibitor; molecular assembly/self assembly; morphogens; multicatalytic endopeptidase complex; mutant; next generation; novel therapeutics; pathogen; prevent; protein degradation; protein function; protein protein interaction; protein structure; ras Proteins; response; small molecule; spelling; tool; tumor initiation; tumorigenesis; ubiquitin-protein ligase

The cellular network and its environment govern cell and organism behavior and are fundamental to the comprehension of function, misfunction and drug discovery. Over the last few years, drugs were observed to often bind to more than one target; thus, poly-pharmacology approaches can be advantageous, complementing the "one drug - one target" strategy. Targeting drug discovery from the systems biology standpoint can help in studies of network effects of mono- and poly-pharmacology. In this mini-review, we provide an overview of the usefulness of network description and tools for mono- and poly-pharmacology, and the ways through which protein interactions can help single- and multi-target drug discovery efforts. We further describe how, when combined with experimental data, modeled structural networks which can predict which proteins interact and provide the structures of their interfaces, can model the cellular pathways, and suggest which specific pathways are likely to be affected. Such structural networks may facilitate structure-based drug design; forecast side effects of drugs; and suggest how the effects of drug binding can propagate in multi-molecular complexes and pathways. We provide an overview of targeted anticancer therapies with small molecule kinase inhibitors. First, we discuss why a single constitutively active kinase emanating from a variety of aberrant genetic alterations is capable of transforming a normal cell, leading it to acquire the hallmarks of a cancer cell. To draw attention to the fact that kinase inhibition in targeted cancer therapeutics differs from conventional cytotoxic chemotherapy, we exploit a conceptual framework explaining why suppressed kinase activity will selectively kill only the so-called oncogene 'addicted' cancer cell, while sparing the healthy cell. Second, we introduce the protein kinase superfamily in light of its common active conformation with precisely positioned structural elements, and the diversified auto-inhibitory conformations among the kinase families. Understanding the detailed activation mechanism of individual kinases is essential to relate the observed oncogenic alterations to the elevated constitutively active state, to identify the mechanism of consequent drug resistance, and to guide the development of the next-generation inhibitors. To clarify the vital importance of structural guidelines in studies of oncogenesis, we explain how somatic mutations in EGFR result in kinase constitutive activation. Third, in addition to the common theme of secondary (acquired) mutations that prevent drug binding from blocking a signaling pathway which is hijacked by the aberrant activated kinase, we discuss scenarios of drug resistance and relapse by compensating lesions that bypass the inactivated pathway in a vertical or horizontal fashion. Collectively, these suggest that the future challenge of cancer therapy with small molecule kinase inhibitors will rely on the discovery of distinct combinations of optimized drugs to target individual subtypes of different cancers. Inflammation, the first line of defense against pathogens can contribute to all phases of tumorigenesis, including tumor initiation, promotion and metastasis. Within this framework, the Toll-like receptor (TLR) pathway plays a central role in inflammation and cancer. Although extremely useful, the classical representation of this, and other pathways in the cellular network in terms of nodes (proteins) and edges (interactions) is incomplete. Structural pathways can help complete missing parts of such diagrams: they demonstrate in detail how signals coming from different upstream pathways merge and propagate downstream, how parallel pathways compensate each other in drug resistant mutants, how multi-subunit signaling complexes form and in particular why they are needed and how they work, how allosteric events can control these proteins and their pathways, and intricate details of feedback loops and how kick in. They can also explain the mechanisms of some oncogenic SNP mutations. Constructing structural pathways is a challenging task. Here, our goal is to provide an overview of inflammation and cancer from the structural standpoint, focusing on the TLR pathway. We use the powerful PRISM (PRotein Interactions by Structural Matching) tool to reveal important structural information of interactions in and within key orchestrators of the TLR pathway, such as MyD88. Allostery is largely associated with conformational and functional transitions in individual proteins. This concept can be extended to consider the impact of conformational perturbations on cellular function and disease states. Here, we clarify the concept of allostery and how it controls physiological activities. We focus on the challenging questions of how allostery can both cause disease and contribute to development of new therapeutics. We aim to increase the awareness of the linkage between disease symptoms on the cellular level and specific aberrant allosteric actions on the molecular level and to emphasize the potential of allosteric drugs in innovative therapies. Allosteric propagation results in communication between distinct sites in the protein structure; it also encodes specific effects on cellular pathways, and in this way it shapes cellular response. One example of long-range effects is binding of morphogens to cell surface receptors, which initiates a cascade of protein interactions that leads to genome activation and specific cellular action. Allosteric propagation results from combinations of multiple factors, takes place through dynamic shifts of conformational ensembles, and affects the equilibria of macromolecular interactions. Here, we (a) emphasize the well-known yet still underappreciated role of allostery in conveying explicit signals across large multimolecular assemblies and distances to specify cellular action; (b) stress the need for quantitation of the allosteric effects; and finally, (c) propose that each specific combination of allosteric effectors along the pathway spells a distinct function. The challenges are colossal; the inspiring reward will be predicting function, misfunction, and outcomes of drug regimes. The ubiquitin-proteasome system (UPS) is involved in many cellular processes including protein degradation. Degradation of a protein via this system involves two successive steps: ubiquitination and degradation. Ubiquitination tags the target protein with ubiquitin-like proteins (UBLs), such as ubiquitin, small ubiquitin-like modifier (SUMO) and NEDD8, via a cascade involving three enzymes: activating enzyme E1, conjugating enzyme E2 and E3 ubiquitin ligases. The proteasomes recognize the UBL-tagged substrate proteins and degrade them. Accumulating evidence indicates that allostery is a central player in the regulation of ubiquitination, as well as deubiquitination and degradation. We provide an overview of the key mechanistic roles played by allostery in all steps of these processes, and highlight allosteric drugs targeting them. We emphasize the crucial mechanistic role played by linkers in allosterically controlling the UPS action by biasing the sampling of the conformational space, which facilitate the catalytic reactions of the ubiquitination and degradation. Finally, we propose that allostery may similarly play key roles in the regulation of molecular machines in the cell, and as such allosteric drugs can be expected to be increasingly exploited in therapeutic regimes. Current focus is on cancer and inflammation pathways including the NF-kB, canonical and non-canonical, the TLR, MyD88, Ras and more.

细胞网络及其环境控制着细胞和生物体的行为，是理解功能、功能失调和药物发现的基础。在过去的几年里，人们发现药物经常与多个靶标结合。因此，多药理学方法可能是有利的，补充了“一种药物 - 一个目标”策略。从系统生物学的角度进行药物发现有助于研究单一和多元药理学的网络效应。在这篇小型评论中，我们概述了网络描述和工具在单一和多重药理学中的有用性，以及蛋白质相互作用如何帮助单靶点和多靶点药物发现工作。我们进一步描述了如何与实验数据相结合，建模的结构网络可以预测哪些蛋白质相互作用并提供其界面的结构，可以对细胞途径进行建模，并建议哪些特定途径可能受到影响。这种结构网络可以促进基于结构的药物设计；预测药物的副作用；并提出药物结合的效应如何在多分子复合物和途径中传播。我们概述了小分子激酶抑制剂的靶向抗癌疗法。首先，我们讨论为什么源自各种异常基因改变的单一组成型活性激酶能够转化正常细胞，导致其获得癌细胞的特征。为了引起人们的注意，靶向癌症治疗中的激酶抑制不同于传统的细胞毒性化疗，我们利用一个概念框架来解释为什么抑制激酶活性将选择性地仅杀死所谓的癌基因“成瘾”癌细胞，同时不伤害健康细胞。其次，我们根据蛋白激酶超家族的共同活性构象和精确定位的结构元件以及激酶家族中多样化的自抑制构象来介绍蛋白激酶超家族。了解各个激酶的详细激活机制对于将观察到的致癌改变与升高的组成性活性状态联系起来、确定随后的耐药机制以及指导下一代抑制剂的开发至关重要。为了阐明结构指南在肿瘤发生研究中的至关重要性，我们解释了 EGFR 的体细胞突变如何导致激酶组成型激活。第三，除了阻止药物结合阻断被异常激活激酶劫持的信号通路的继发（获得性）突变这一共同主题之外，我们还讨论了通过以垂直或水平方式绕过失活通路的补偿性病变来产生耐药性和复发的情况。总的来说，这些表明小分子激酶抑制剂癌症治疗的未来挑战将依赖于发现针对不同癌症的个体亚型的优化药物的独特组合。炎症是抵抗病原体的第一道防线，可促进肿瘤发生的所有阶段，包括肿瘤的发生、促进和转移。在此框架内，Toll 样受体 (TLR) 通路在炎症和癌症中发挥着核心作用。尽管非常有用，但这种路径以及细胞网络中的其他路径在节点（蛋白质）和边缘（相互作用）方面的经典表示是不完整的。结构途径可以帮助完成此类图表中缺失的部分：它们详细展示了来自不同上游途径的信号如何向下游合并和传播，平行途径如何在耐药突变体中相互补偿，多亚基信号复合物如何形成，特别是为什么需要它们以及它们如何工作，变构事件如何控制这些蛋白质及其途径，以及反馈循环的复杂细节以及如何发挥作用。它们还可以解释 一些致癌 SNP 突变的机制。构建结构路径是一项具有挑战性的任务。在这里，我们的目标是从结构角度概述炎症和癌症，重点关注 TLR 通路。我们使用强大的 PRISM（结构匹配蛋白质相互作用）工具来揭示 TLR 通路关键协调器（例如 MyD88）内部和内部相互作用的重要结构信息。变构很大程度上与单个蛋白质的构象和功能转变有关。这个概念可以扩展到考虑构象扰动对细胞功能和疾病状态的影响。在这里，我们阐明变构的概念以及它如何控制生理活动。我们关注变构如何引起疾病并促进新疗法开发的挑战性问题。我们的目标是提高人们对细胞水平上的疾病症状与分子水平上的特定异常变构作用之间联系的认识，并强调变构药物在创新疗法中的潜力。变构传播导致蛋白质结构中不同位点之间的通讯；它还编码对细胞途径的特定影响，并以这种方式塑造细胞反应。远程效应的一个例子是形态发生素与细胞表面受体的结合，这启动了一系列蛋白质相互作用，导致基因组激活和特定的细胞作用。变构传播是多种因素组合的结果，通过构象整体的动态变化发生，并影响大分子相互作用的平衡。在这里，我们（a）强调变构在跨大型多分子组装体和距离传递明确信号以指定细胞作用方面的众所周知但仍被低估的作用； (b) 强调变构效应定量的必要性；最后，（c）提出，沿该通路的变构效应子的每个特定组合都具有不同的功能。挑战是巨大的；令人鼓舞的奖励将是预测药物治疗方案的功能、功能障碍和结果。泛素蛋白酶体系统 (UPS) 参与许多细胞过程，包括蛋白质降解。通过该系统降解蛋白质涉及两个连续步骤：泛素化和降解。泛素化通过涉及三种酶的级联，用泛素样蛋白 (UBL)（例如泛素、小泛素样修饰剂 (SUMO) 和 NEDD8）标记靶蛋白：激活酶 E1、缀合酶 E2 和 E3 泛素连接酶。蛋白酶体识别 UBL 标记的底物蛋白并降解它们。越来越多的证据表明，变构是泛素化、去泛素化和降解调节的核心角色。我们概述了变构在这些过程的所有步骤中所发挥的关键机制作用，并重点介绍了针对这些过程的变构药物。我们强调连接子通过偏置构象空间采样来变构控制 UPS 作用所发挥的关键机制作用，从而促进泛素化和降解的催化反应。最后，我们提出变构可能在细胞分子机器的调节中同样发挥关键作用，因此变构药物有望在治疗方案中得到越来越多的利用。目前的重点是癌症和炎症通路，包括 NF-kB、规范和非规范、TLR、MyD88、Ras 等。