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 研究计划摘要 阿片类生物碱最强大的镇痛和成瘾特性由µOR介导。 μOR是阿片作用的主要受体，是最古老的药物之一 药典中的目标。阿片受体是高度通用的信号分子。 μOR的激活导致通过异源三聚体G蛋白Gi的信号传导，导致 镇痛和镇静以及欣快和身体依赖。μOR还可以发出信号 通过抑制蛋白，这一途径已被归因于阿片类镇痛药的不良反应 包括耐受性呼吸抑制和便秘μOR一直是 在过去的世纪里，人们对药物发现的高度关注， 不同功效的配体。这些药物占据了广泛的化学谱，从小的有机 分子到各种内源性和合成肽。最近的研究表明， 药物可能在促进Gi或抑制蛋白途径激活的能力上有所不同， 称之为“偏见”。最近已经表明，Gi偏向的药物，如PZM 21，鉴定 在初始资助期内，可能比无偏见激动剂具有更好的治疗效果 例如吗啡。该奖项资助的研究目标是提供结构性见解， 这将有助于我们开发下一代阿片类镇痛药的能力 副作用更少，成瘾性更低 下一个供资期的具体目标（在《进展报告》末尾有更详细的说明） 报告） 目标1.确定与Gi复合的阿片受体的结构。 目标2.确定与G蛋白偏向激动剂结合的µOR的结构。 目标3.确定阿片受体与抑制蛋白复合物的结构。 目标4。表征不同配体对µOR结构和动力学的影响。 资源共享计划： 我们将分享在我们的研究过程中产生的所有材料。这些将免费分发， 或在发表后立即发表，我们将根据要求提供相关方案和发表的数据。 材料转让的限制性条款不得超过简单信函协议（SLA）或 统一生物材料转移协议（UBMTA），且不符合要求。 我们将遵守NIH关于共享独特研究资源的资助政策，包括 NIH赠款和合同接受者的生物医学研究资源原则和指南 1999年12月印发（http：//www.ott.nih.gov/policy/rt_guide_final.html）。任何知识分子 如果出现需要专利的财产，我们将确保技术（材料和数据） 根据NIH原则和指南文件，广泛提供给研究界。 此外，晶体学坐标和3D电子显微镜图将存放到蛋白质 数据库（PDB）和电子显微镜数据库（EMDB）。