Structural Determinants of Kappa Opioid Receptor Signaling

项目概要/摘要 G 蛋白偶联受体 (GPCR) 是人类基因组中最大的一类受体，可以发出信号 通过多种传感器，包括异源三聚体 G 蛋白和 β-抑制蛋白。阿片受体是 GPCR 它们在疼痛感觉中的作用使其成为止痛药（如羟考酮和 吗啡。然而，阿片类药物具有极高的滥用潜力，并且经常引起致命的副作用，例如 呼吸停止和死亡。这些问题的严重性导致人们寻找阿片类药物替代品来治疗 疼痛和相关病症。阿片受体的激活会激活下游效应器，包括多个 G 蛋白（Gi1、Gi2、Gi3、GoA、GoB、Gz 和 Ggustducin）和 β-arrestin（β-arrestin1 和 β-arrestin2）。一个专业 差距是对阿片受体如何识别不同传感器和功能的不完全理解 通过每个途径的信号传导的影响。 Kappa 阿片受体（KOR）显示出有前景的治疗作用 因其新颖的镇痛活性而具有潜力——靶向 KOR 的药物不会导致成瘾或导致死亡 由于从 mu 阿片受体激动剂观察到过量。选择性 KOR 拮抗剂也已被 进行治疗成瘾和抑郁症的临床试验。我实验室的研究是由 总体假设是受体-配体/传感器复合物的大规模结构测定研究将 提供对阿片受体信号传导的分子水平见解，并促进新型药物的设计和优化 配体支架可以进一步开发成具有所需行为特征的新药。通过组合 X- 射线晶体学、冷冻电镜和分子药理学，我们将阐明 KOR 的基本机制 配体选择性、受体激活和信号传导。为此，我们将遵循以下主要方向：（一） 确定不同阿片受体类型之间配体选择性的结构决定因素，(ii) 确定 不同 G 蛋白亚型识别的分子基础，以及 (iii) 识别负责的结构特征 抑制蛋白结合的激活态。长期目标是开发受体特异性和通路选择性探针 使用基于结构的药物发现并研究体内个体阿片受体信号传导的功能。

Project Summary/Abstract G protein-coupled receptors (GPCRs) are the largest class of receptors in the human genome and can signal through multiple transducers, including heterotrimeric G protein and β-arrestins. Opioid receptors are GPCRs whose role in pain sensation has made them primary drug targets for pain medications such as oxycodone and morphine. However, opioids have exceptionally high abuse potential and often cause fatal side effects such as respiratory arrest and death. The magnitude of these problems has led to a search for opioid alternatives to treat pain and related conditions. Activation of opioid receptors activates downstream effectors, including multiple G proteins (Gi1, Gi2, Gi3, GoA, GoB, Gz, and Ggustducin) and β-arrestins (β-arrestin1 and β-arrestin2). A major gap is an incomplete understanding of how opioid receptors recognize different transducers and the functional effects of signaling through each pathway. Kappa opioid receptor (KOR) has displayed promising therapeutic potential because of its novel analgesic activity –drugs that target KOR do not lead to addiction or cause death due to overdose as observed from mu opioid receptor agonists. Selective KOR antagonists have also been pursued in clinical trials for the treatment of addiction and depression. The research in my lab is driven by the overall hypothesis that large-scale structural determination studies of receptor-ligand/transducer complexes will provide molecular-level insights into opioid receptor signaling, and facilitate the design and optimization of novel ligand scaffolds that could be further developed into new drugs with desired behavior profile. By combining X- ray crystallography, Cryo-EM, and molecular pharmacology, we will elucidate fundamental mechanisms of KOR ligand selectivity, receptor activation and signaling. To do so, we will pursue the following main directions: (i) identify structural determinants of ligand selectivity between different opioid receptors types, (ii) identify the molecular basis for different G protein subtypes recognition, and (iii) identify structural features responsible for arrestin-bound activating states. The long-term goal is to develop receptor-specific and pathway-selective probes using structure-based drug discovery and study the function of individual opioid receptor signaling in vivo.