Structure of the µ-opioid receptor–Gi protein complex,Nature

当前位置： X-MOL 学术 › Nature › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Structure of the µ-opioid receptor–Gi protein complex
Nature ( IF 50.5 ) Pub Date : 2018-06-01 , DOI: 10.1038/s41586-018-0219-7
Antoine Koehl ₁ , Hongli Hu _{1,

2} , Shoji Maeda ₂ , Yan Zhang _{1,

2} , Qianhui Qu _{1,

2} , Joseph M Paggi _{1,

2,

3,

4} , Naomi R Latorraca _{1,

2,

3,

4,

5} , Daniel Hilger ₂ , Roger Dawson ₆ , Hugues Matile ₆ , Gebhard F X Schertler _{7,

8} , Sebastien Granier ₉ , William I Weis _{1,

2} , Ron O Dror _{1,

2,

3,

4,

5} , Aashish Manglik _{10,

11} , Georgios Skiniotis _{1,

2} , Brian K Kobilka ₂

Affiliation

Department of Structural Biology, Stanford University School of Medicine, Stanford, CA, USA.
Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA.
Department of Computer Science, Stanford University, Stanford, CA, USA.
Institute for Computational and Mathematical Engineering, Stanford University, Stanford, CA, USA.
Biophysics Program, Stanford University, Stanford, CA, USA.
Roche Pharma Research and Early Development, Therapeutic Modalities, Roche Innovation Center Basel, F.Hoffmann-La Roche, Basel, Switzerland.
Laboratory of Biomolecular Research, Paul Scherrer Institute, Villigen, Switzerland.
Department of Biology, ETH Zürich, Zürich, Switzerland.
Institut de Génomique Fonctionnelle, INSERM, Montpellier, France.
Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA, USA.
Department of Anesthesia and Perioperative Care, University of California San Francisco, San Francisco, CA, USA.

The μ-opioid receptor (μOR) is a G-protein-coupled receptor (GPCR) and the target of most clinically and recreationally used opioids. The induced positive effects of analgesia and euphoria are mediated by μOR signalling through the adenylyl cyclase-inhibiting heterotrimeric G protein Gi. Here we present the 3.5 Å resolution cryo-electron microscopy structure of the μOR bound to the agonist peptide DAMGO and nucleotide-free Gi. DAMGO occupies the morphinan ligand pocket, with its N terminus interacting with conserved receptor residues and its C terminus engaging regions important for opioid-ligand selectivity. Comparison of the μOR–Gi complex to previously determined structures of other GPCRs bound to the stimulatory G protein Gs reveals differences in the position of transmembrane receptor helix 6 and in the interactions between the G protein α-subunit and the receptor core. Together, these results shed light on the structural features that contribute to the Gi protein-coupling specificity of the µOR.A cryo-electron structure of the µ-opioid receptor in complex with the peptide agonist DAMGO and the inhibitory G protein Gi reveals structural determinants of its G protein-binding specificity.

中文翻译：

µ-阿片受体-Gi 蛋白复合物的结构

μ-阿片受体 (μOR) 是一种 G 蛋白偶联受体 (GPCR)，也是大多数临床和娱乐用途阿片类药物的靶标。镇痛和欣快感的诱导积极作用是通过腺苷酸环化酶抑制异三聚体 G 蛋白 Gi 的 μOR 信号介导的。在这里，我们展示了与激动剂肽 DAMGO 和无核苷酸 Gi 结合的 μOR 的 3.5 Å 分辨率冷冻电子显微镜结构。 DAMGO 占据吗啡喃配体口袋，其 N 末端与保守的受体残基相互作用，其 C 末端接合对阿片类药物配体选择性很重要的区域。将μOR-Gi复合物与先前确定的与刺激性G蛋白Gs结合的其他GPCR的结构进行比较，揭示了跨膜受体螺旋6的位置以及G蛋白α亚基与受体核心之间的相互作用的差异。总之，这些结果揭示了有助于 µOR 的 Gi 蛋白偶联特异性的结构特征。 µ-阿片受体与肽激动剂 DAMGO 和抑制性 G 蛋白 Gi 复合的冷冻电子结构揭示了结构决定因素其 G 蛋白结合特异性。

更新日期：2018-06-01

点击分享查看原文

点击收藏

公开下载

阅读更多本刊最新论文本刊介绍/投稿指南11