Structural Basis of Opioid Receptor Function

少年派：布莱恩·科比尔卡 阿片受体功能的结构基础 研究计划摘要 阿片类生物碱最强的止痛和成瘾特性是由µOR调节的。 作为主要负责鸦片效应的受体，μOR是最古老的药物之一 药典中的目标。阿片受体是一种用途广泛的信号分子。 μOR的激活导致通过异三聚体G蛋白Gi的信号传递，从而导致 止痛和镇静，以及欣快和身体依赖。μOR还可以发出信号 通过arrestin，这一途径被归因于阿片类镇痛剂的副作用 包括耐受性、呼吸抑制和便秘。μOR一直是 在过去的一个世纪里，对药物发现工作的高度关注，确定了许多 不同效力的配体。这些药物占据了广泛的化学光谱，从小型有机药物 分子中含有多种内源性和合成肽。最近有证据表明， 药物在促进GI或arrestin通路激活的能力上可能不同，这是一种属性 指的是一种“偏见”。最近有研究表明，PZM21等对胃肠道有偏见的药物 在最初的资助期，可能比无偏向的激动剂有更好的治疗方案 比如吗啡。由该奖项资助的研究的目标是提供对 有偏见的信号将有助于我们开发下一代阿片类止痛药的能力 副作用更少，上瘾的可能性也更小。 下一阶段供资的具体目标(在进展结束时更详细地说明 报告) 目的1.确定阿片受体在胃肠道中的结构。 目的2.确定G蛋白偏向激动剂结合的µOR的结构。 目的3.确定阿片受体与arrestin络合物的结构。 目标4.描述不同配体对µOR结构和动力学的影响。 资源共享计划： 我们将分享我们在学习过程中产生的所有材料。这些将在之前免费分发 或在发布后立即发布，我们将根据要求提供相关协议和发布的数据。 材料转让将不会有比简单信函协议(SLA)或 《统一生物材料转让协议》(UBMTA)和无REACH直通要求。 我们将坚持国家卫生研究院关于共享独特研究资源的拨款政策，包括共享 美国国立卫生研究院资助和合同接受者的生物医学研究资源原则和指南 1999年12月发出(http://www.ott.nih.gov/policy/rt_guide_final.htmlȌ.是否应该有任何知识分子 如果出现需要专利的财产，我们将确保技术(材料和数据)保留 根据美国国立卫生研究院的原则和指南文件，广泛提供给研究界。 此外，晶体坐标和3d电子显微镜地图将被存放在蛋白质上 数据库(PDB)和电子显微镜数据库(EMDB)。

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.