Discovering the mechanism of GPCR-mediated arrestin stimulation to enable effective drug therapies

发现 GPCR 介导的抑制蛋白刺激机制以实现有效的药物治疗

• 批准号: 10092188
• 负责人: Ron Dror
• 金额: $ 30.94万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10092188
• 关键词: Academia; Address; Adopted; Affect; Alzheimer' s Disease; Arrestins; Binding; Binding Proteins; Biological; Biophysics; C-terminal; Cardiovascular Diseases; Cardiovascular system; Collaborations; Complex; Computers; Coupling; Crystallization; Crystallography; Dangerousness; Dependence; Development; Diabetes Mellitus; Disease; Dissociation; Drug Industry; Drug Receptors; Drug Targeting; Electron Spin Resonance Spectroscopy; Electrons; Event; Family; Fluorescence Spectroscopy; Foundations; G-Protein-Coupled Receptors; GTP-Binding Protein alpha Subunits, Gs; GTP-Binding Proteins; Goals; Inflammation; Lead; Ligands; Lung; Lung diseases; Malignant Neoplasms; Mediating; Medicine; Metabolic Diseases; Methods; Molecular; Molecular Conformation; Obesity; Pathway interactions; Pattern; Pharmaceutical Preparations; Pharmacotherapy; Phosphorylation; Process; Property; Proteins; Publications; Research; Research Personnel; Resolution; Shapes; Signal Pathway; Signal Transduction; Structure; Surface; Tail; Techniques; Work; base; computer studies; design; drug discovery; effective therapy; experimental group; experimental study; molecular dynamics; neuropsychiatric disorder; novel therapeutics; protein activation; receptor; receptor binding; receptor coupling; recruit; scaffold; side effect; simulation; single-molecule FRET; structural biology; trafficking

Project Summary Medicines that cause G protein–coupled receptors (GPCRs) to selectively stimulate arrestins, or to selectively avoid stimulation of arrestins, promise more effective and safer treatments for a wide variety of diseases, including neuropsychiatric, cardiovascular, pulmonary and metabolic disorders. Despite intense study of GPCR–arrestin interactions in both academia and the pharmaceutical industry, and despite dramatic recent advances in the structural biology of GPCRs and arrestins, the mechanism by which GPCRs stimulate arrestins remains poorly understood. Likewise, the means by which GPCRs might achieve selectivity for or against arrestin signaling remains unclear. The proposed research will utilize atomic-level molecular dynamics simulations to address these challenges, thereby providing a foundation for the design of functionally selective GPCR-targeted drugs with desired effects on arrestins. Aim 1 is to determine the activation mechanism of arrestin, pinpointing which of the GPCR– arrestin interaction surfaces drives arrestin activation and discovering the allosteric coupling between regions of arrestin that causes these structural changes to take place. The remaining aims are to determine the effect of both GPCR conformation (Aim 2) and GPCR phosphorylation pattern (Aim 3) on arrestin binding and activation. This will reveal how a GPCR can favor or disfavor arrestin recruitment and signaling relative to G protein recruitment and signaling. It will also reveal how a GPCR can favor specific arrestin conformations, potentially stimulating some of arrestin’s downstream effects without stimulating others. The proposed research will rely on state-of-the-art simulation methods that have recently enabled the determination of functional mechanisms of GPCRs, G proteins, transporters, and other proteins. It will also benefit from close collaborations with multiple experimentalists: results from crystallography, fluorescence spectroscopy, NMR, electron paramagnetic resonance, and cell signaling experiments will combine to both guide and validate the simulations. This proposal is significant not only because it will illuminate a quintessential biological signaling process but also because it will reveal a key part of the structural basis for functional selectivity at GPCRs. It will thus provide a foundation for the rational design of safer and more effective medications acting at GPCRs, which are by far the largest class of drug targets.

项目摘要 引起G蛋白与偶联受体（GPCR）的药物有选择地刺激了逮捕蛋白，或 为了有选择地避免刺激逮捕蛋白，请保证更有效，更安全的治疗 各种各样的疾病，包括神经精神病，心血管，肺和代谢 疾病。尽管对学术界和学术界的GPCR - arrestin相互作用进行了深入研究 制药行业，并首选的巨大最新进展 GPCR和逮捕蛋白，GPCR刺激逮捕蛋白的机制较差 理解齿。同样，GPCR可能对或反对的选择性 逮捕信号仍然不清楚。拟议的研究将利用原子级分子 解决这些挑战的动力模拟，从而为 功能性选择性靶向GPCR的药物的设计对逮捕蛋白有预期的作用。 目的1是确定抑制蛋白的激活机制，指出GPCR的哪个 逮捕蛋白相互作用表面驱动逮捕蛋白激活并发现变构耦合 在逮捕区域之间导致这些结构性变化发生的区域。其余 目的是确定GPCR构象（AIM 2）和GPCR的影响 磷酸化模式（AIM 3）在抑制蛋白结合和激活上。这将揭示GPCR如何 相对于G蛋白招募和 信号。它还将揭示GPCR如何偏爱特定的逮捕素构象，并有可能 刺激某些逮捕蛋白的下游效果而不刺激其他效果。 拟议的研究将依赖于最近具有的最新模拟方法 能够确定GPCR，G蛋白，转运蛋白和 其他蛋白质。它也将受益于与多个实验者的密切合作：结果 从晶体学，荧光光谱，NMR，电子顺磁共振和 细胞信号传导实验将结合指导并验证模拟。这个建议 之所以重要，不仅是因为它会阐明典型的生物信号传导过程，还会阐明 这也将是因为它将揭示GPCR功能选择性的结构基础的关键部分。 因此，将为更安全，更有效的药物的合理设计提供基础 在GPCR中作用，这是迄今为止最大的药物靶标。