Structural Basis of Opioid Receptor Function

阿片受体功能的结构基础

• 批准号: 9924823
• 负责人: Brian K Kobilka
• 金额: $ 15.26万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-15 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9924823
• 关键词: 3-Dimensional; Absence of pain sensation; Adverse effects; Affinity; Agonist; Agreement; Analgesics; Arrestins; Award; Behavior; Binding; Biocompatible Materials; Biomedical Research; Chemicals; Communities; Complex; Constipation; Core Protein; Cryoelectron Microscopy; Crystallization; Crystallography; Data; Deposition; Drug Targeting; Electron Microscopy; Electrons; Ensure; Euphoria; Exhibits; Funding; G-Protein-Coupled Receptors; GTP-Binding Protein alpha Subunits, Gs; GTP-Binding Proteins; Goals; Grant; Guidelines; Heterotrimeric GTP-Binding Proteins; Intellectual Property; Label; Legal patent; Letters; Libraries; Ligands; Lysine; Maps; Measures; Mediating; Methionine; Molecular Conformation; Morphine; Movement; Muscarinic M2 Receptor; NIH Grants and Contracts; Opioid Analgesics; Opioid Receptor; Opium; Pathway interactions; Peptides; Pharmaceutical Preparations; Pharmacopoeias; Physical Dependence; Policies; Progress Reports; Property; Proteins; Protocols documentation; Publications; Publishing; Receptor Signaling; Research; Resolution; Resource Sharing; Resources; Sedation procedure; Signal Transduction; Signaling Molecule; Spectrum Analysis; Structure; Technology; Therapeutic; United States National Institutes of Health; beta-2 Adrenergic Receptors; data warehouse; delta opioid receptor; desensitization; drug discovery; insight; material transfer agreement; mimetics; mu opioid receptors; nanobodies; next generation; off-patent; opiate alkaloid; protein complex; receptor; receptor function; respiratory; small molecule; synthetic peptide

PI: Brian Kobilka Structural Basis for Opioid Receptor Function Abstract of Research Plan The most powerful analgesic and addictive properties of opiate alkaloids are mediated by the µOR. As the receptor primarily responsible for the effects of opium, the μOR is one of the oldest drug targets within the pharmacopeia. Opioid receptors are highly versatile signaling molecules. Activation of the μOR results in signaling through the heterotrimeric G protein Gi, resulting in analgesia and sedation as well as euphoria and physical dependence. The μOR can also signal through arrestin, and this pathway has been attributed to adverse effects of opioid analgesics including tolerance, respiratory suppression, and constipation. The μOR has been the subject of intense focus for drug-discovery efforts over the past century, with the identification of numerous ligands of varying efficacy. These drugs occupy a wide chemical spectrum, from small organic molecules to a variety of endogenous and synthetic peptides. Recently it has been shown that drugs may differ in their ability to promote activation of the Gi or arrestin pathways, a property referred to a “bias”. It has recently been shown that Gi-biased drugs such as PZM21, identified during the initial funding period, may have better therapeutic profiles than non-biased agonists such as morphine. The goal of research funded by this award is to provide structural insights into biased signaling that will facilitate our ability to develop the next generation of opioid analgesics with fewer adverse effects and less addictive potential. Specific Aims for the next period of funding (described in more detail at the end of the Progress Report) Aim 1. Determine the structure of an opioid receptor in complex with Gi. Aim 2. Determine the structure of the µOR bound to a G protein biased agonist. Aim 3. Determine the structure of an opioid receptor in complex with arrestin. Aim 4 . Characterize the effect of different ligands on µOR structure and dynamics. Resource Sharing Plan: We will share all materials generated during the course of our studies. These will be distributed freely before or immediately after publication, and we will provide relevant protocols and published data upon request. Material transfers will be made with no more restrictive terms than in the Simple Letter Agreement (SLA) or the Uniform Biological Materials Transfer Agreement (UBMTA) and without reach through requirements. We will adhere to the NIH Grant Policy on Sharing of Unique Research Resources including the Sharing of Biomedical Research Resources Principles and Guidelines for Recipients of NIH Grants and Contracts issued in December, 1999 (http://www.ott.nih.gov/policy/rt_guide_final.htmlȌ. Should any intellectual property arise which requires a patent, we will ensure that the technology (materials and data) remains widely available to the research community in accordance with the NIH Principles and Guidelines document. In addition, crystallographic coordinates and 3D electron microscopy maps will be deposited to the Protein Data Bank (PDB) and the Electron Microscopy Data Bank (EMDB), respectively.

PI：Brian Kobilka 阿片受体功能的结构基础 研究摘要 优化生物碱的最强大的镇痛和添加特性是由µOR介导的。 由于接收器主要负责鸦片的影响，因此μor是最古老的药物之一 药房内的目标。阿片受体是高度用途的信号分子。 μOR的激活导致通过异三聚体G蛋白GI发出信号，从而导致 镇痛和镇静以及欣快感和身体依赖。 μor也可以发出信号 通过逮捕蛋白，该途径归因于阿片类镇痛药的不良影响 包括公差，呼吸抑制和便秘。 μor是 在过去的一个世纪中，强烈专注于药物发现的努力，并确定了许多 不同效率的配体。这些药物占据了较宽的化学谱，来自小有机物 分子到各种内源性和合成胡椒中。最近已经表明 毒品的促进gi或停滞途径激活的能力可能有所不同，该途径是一种特性 提到“偏见”。最近已经显示，gi偏见的药物（例如PZM21）已鉴定出来 在最初的资金期间，可能比无偏激动剂具有更好的治疗特征 例如吗啡。该奖项资助的研究的目的是提供结构性见解 有偏见的信号传导将有助于我们发展下一代阿片类镇痛药的能力 不良影响较少，添加潜力较小。 针对下一个阶段的具体目的（进度结束时更详细地描述 报告） AIM 1。确定与GI复合物中阿片类药物受体的结构。 目标2。确定与G蛋白偏置激动剂结合的结构。 目标3。确定与抑制蛋白复合物中阿片类药物受体的结构。 AIM 4。表征不同配体对µOR结构和动力学的影响。 资源共享计划： 我们将共享研究过程中生成的所有材料。这些将在之前自由分发 或出版后立即，我们将根据要求提供相关的协议并发布数据。 物料转移将不得与简单的信件协议（SLA）或 统一的生物材料转移协议（UBMTA），没有要求。 我们将遵守NIH赠款政策，以共享独特的研究资源，包括共享 NIH赠款和合同的收件人生物医学研究资源原则和指南 于1999年12月发布（http://www.ott.nih.gov/policy/rt_guide_final.htmlȍ。 出现需要专利的财产，我们将确保技术（材料和数据）仍然存在 根据NIH原则和指南文件，研究界广泛使用。 此外，将将晶体学坐标和3D电子显微镜图沉积到蛋白 数据库（PDB）和电子显微镜数据库（EMDB）。