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.

项目概要 导致 G 蛋白偶联受体 (GPCR) 选择性刺激抑制蛋白的药物，或 选择性地避免抑制蛋白的刺激，承诺更有效和更安全的治疗方法 多种疾病，包括神经精神疾病、心血管疾病、肺疾病和代谢疾病 尽管学术界和医学界对 GPCR-arrestin 相互作用进行了大量研究。 制药业，尽管结构生物学最近取得了巨大进展 GPCR 和抑制蛋白，GPCR 刺激抑制蛋白的机制仍然很差 同样，也了解 GPCR 可能实现支持或反对的选择性的方式。 抑制蛋白信号传导仍不清楚。拟议的研究将利用原子水平的分子。 动力学模拟来应对这些挑战，从而为 设计对抑制蛋白具有预期效果的功能选择性 GPCR 靶向药物。 目标 1 是确定视紫红质抑制蛋白的激活机制，查明 GPCR 中的哪一个– 视紫红质抑制蛋白相互作用表面驱动视紫红质抑制蛋白激活并发现变构耦合 导致这些结构变化发生的抑制蛋白区域之间。 目的是确定 GPCR 构象（目标 2）和 GPCR 的影响 视紫红质抑制蛋白结合和激活的磷酸化模式（目标 3） 这将揭示 GPCR 是如何进行的。 可以有利于或不利于抑制蛋白募集和与 G 蛋白募集相关的信号传导 它还将揭示 GPCR 如何有利于特定的抑制蛋白构象。 刺激抑制蛋白的一些下游效应而不刺激其他效应。 拟议的研究将依赖于最近出现的最先进的模拟方法 能够确定 GPCR、G 蛋白、转运蛋白和 其他蛋白质也将受益于与多个实验者的密切合作：结果。 来自晶体学、荧光光谱、核磁共振、电子顺磁共振和 细胞信号传导实验将结合起来指导和验证该提议。 意义重大，不仅因为它将阐明典型的生物信号传导过程，而且 还因为它将揭示 GPCR 功能选择性结构基础的关键部分。 从而为合理设计更安全、更有效的药物提供基础 作用于 GPCR，这是迄今为止最大的一类药物靶点。