Structural Determinants of Kappa Opioid Receptor Signaling

Kappa 阿片受体信号传导的结构决定因素

• 批准号: 10798613
• 负责人: Tao Che
• 金额: $ 12.04万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10798613
• 关键词: Agonist; Analgesics; Arrestins; Behavior; Binding; Cause of Death; Cessation of life; Chemicals; Clinical Treatment; Clinical Trials; Complex; Cryoelectron Microscopy; Data; Drug Targeting; G-Protein-Coupled Receptors; GTP-Binding Proteins; Goals; Heterotrimeric GTP-Binding Proteins; Human Genome; Individual; Ligands; Mental Depression; Molecular; Mood Disorders; Morphine; Opioid; Opioid Antagonist; Opioid Receptor; Opioid agonist; Overdose; Oxycodone; Pain; Pain management; Pathway interactions; Pharmacology; Receptor Activation; Receptor Signaling; Research; Role; Signal Transduction; Structure; System; Therapeutic; Transducers; X-Ray Crystallography; abuse liability; addiction; antagonist; beta-arrestin; design; drug discovery; in vivo; insight; kappa opioid receptors; mu opioid receptors; novel; novel therapeutics; pain sensation; pharmacologic; receptor; respiratory; scaffold; side effect; structural determinants

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.

项目总结/摘要 G蛋白偶联受体（GPCR）是人类基因组中最大的一类受体， 包括异源三聚体G蛋白和β-抑制蛋白。阿片受体是GPCR 其在疼痛感觉中的作用使其成为止痛药如羟考酮的主要药物靶标， 吗啡然而，阿片类药物具有极高的滥用潜力，经常引起致命的副作用，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 疼痛及相关症状。阿片受体的激活激活下游效应子，包括多个G 蛋白质（Gi 1、Gi 2、Gi 3、果阿、GoB、Gz和Ggustducin）和β-抑制蛋白（β-抑制蛋白1和β-抑制蛋白2）。一个主要 差距是一个不完整的理解阿片受体如何识别不同的转换器和功能 通过每一个信号通路的影响。κ阿片受体（KOR）已显示出很有前途的治疗作用 潜在的，因为它的新的镇痛活性-药物的目标KOR不会导致成瘾或导致死亡 这是由于从μ阿片受体激动剂中观察到的过量。选择性KOR拮抗剂也已被 用于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，受体-配体/转导子复合物的大规模结构测定研究将 提供阿片受体信号传导的分子水平的见解，并促进新的药物的设计和优化。 配体支架，可以进一步开发成具有所需行为特征的新药。通过结合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、受体活化和信号传导。为此，我们会朝以下主要方向努力：（i） 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）确定负责 抑制蛋白结合激活状态。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和研究个体阿片受体在体内的功能信号传导。

项目成果

GPCR-G protein selectivity revealed by structural pharmacology.

结构药理学揭示 GPCR-G 蛋白选择性。

• DOI: 10.1111/febs.17049
• 发表时间: 2023
• 期刊: The FEBS journal
• 作者: Bernhard,SarahM;Han,Jianming;Che,Tao
• 通讯作者: Che,Tao

Molecular mechanism of biased signaling at the kappa opioid receptor.

• DOI: 10.1038/s41467-023-37041-7
• 发表时间: 2023-03-11
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: El Daibani, Amal;Paggi, Joseph M. M.;Kim, Kuglae;Laloudakis, Yianni D. D.;Popov, Petr D.;Bernhard, Sarah M. M.;Krumm, Brian E. E.;Olsen, Reid H. J.;Diberto, Jeffrey;Carroll, F. Ivy;Katritch, Vsevolod;Wuensch, Bernhard;Dror, Ron O. O.;Che, Tao
• 通讯作者: Che, Tao

Spotlight on Nociceptin/Orphanin FQ Receptor in the Treatment of Pain.

• DOI: 10.3390/molecules27030595
• 发表时间: 2022-01-18
• 期刊: Molecules (Basel, Switzerland)
• 作者: El Daibani A;Che T
• 通讯作者: Che T