Structural Basis of Opioid Receptor Function

阿片受体功能的结构基础

基本信息

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
项目类别：
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

项目摘要

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：布莱恩·科比尔卡阿片受体功能的结构基础研究计划摘要阿片生物碱最强大的镇痛和成瘾特性是由 µOR 介导的。作为主要负责鸦片作用的受体，μOR 是最古老的药物之一阿片受体是药典中用途广泛的信号分子。 μOR 的激活导致通过异源三聚体 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性也可以发出信号。通过抑制蛋白，该途径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 一直是研究的主题。在过去的一个世纪里，药物发现工作得到了高度关注，并发现了许多这些药物具有广泛的化学谱，从小有机物。最近已经表明，多种内源性和合成肽的分子。它们促进 Gi 或抑制蛋白途径激活的能力可能有所不同，这是一种特性最近发现，PZM21 等 Gi 偏向药物已被识别。在初始资助期间，可能比无偏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见解。偏向信号将有助于我们开发下一代阿片类镇痛药的能力不良反应较少，成瘾可能性也较小。下一期资助的具体目标（在进展末尾有更详细的描述）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：我们将分享我们学习过程中产生的所有材料，这些材料将在之前免费分发。或在发布后立即提供，我们将根据要求提供相关方案和发布的数据。材料转让的限制性条款不会比简单信件协议 (SLA) 或统一生物材料转让协议 (UBMTA) 且未达到要求。我们将遵守 NIH 关于共享独特研究资源的拨款政策，包括共享 NIH 拨款和合同接受者的生物医学研究资源原则和指南 1999 年 12 月发布（http://www.ott.nih.gov/policy/rt_guide_final.html?。如果任何知识分子财产的产生需要专利，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，广泛向研究界提供。此外，晶体坐标和 3D 电子显微镜图将被存入蛋白质分别是数据库（PDB）和电子显微镜数据库（EMDB）。