Cryo-EM structure of small-molecule agonist bound delta opioid receptor-Gi complex enables discovery of biased compound
Delta opioid receptor (δOR) plays a pivotal role in modulating human sensation and emotion. It is an attractive target for drug discovery since, unlike Mu opioid receptor, it is associated with low risk of drug dependence. Despite its potential applications, the pharmacological properties of δOR, including the mechanisms of activation by small-molecule agonists and the complex signaling pathways it engages, as well as their relation to the potential side effects, remain poorly understood. In this study, we use cryo-electron microscopy (cryo-EM) to determine the structure of the δOR-G<sub>i</sub> complex when bound to a small-molecule agonist (ADL5859). Moreover, we design a series of probes to examine the key receptor-ligand interaction site and identify a region involved in signaling bias. Using ADL06 as a chemical tool, we elucidate the relationship between the β-arrestin pathway of the δOR and its biological functions, such as analgesic tolerance and convulsion activities. Notably, we discover that the β-arrestin recruitment of δOR might be linked to reduced gastrointestinal motility. These insights enhance our understanding of δOR's structure, signaling pathways, and biological functions, paving the way for the structure-based drug discovery.
Authors
- Chanjuan Xu (ORCID: https://orcid.org/0000-0002-5640-1896)
- Zhenhua Shao (ORCID: https://orcid.org/0000-0001-7204-801X)
- Shilong Hu
- Bowen Ke (ORCID: https://orcid.org/0000-0002-0328-7719)
- Chang Zhao (ORCID: https://orcid.org/0000-0002-8273-1338)
- Runduo Liu (ORCID: https://orcid.org/0000-0002-8446-0404)
- Yuxuan Liu (ORCID: https://orcid.org/0000-0001-9162-7885)
- Jianfeng Liu (ORCID: https://orcid.org/0000-0002-0284-8377)
- Zhe Li (ORCID: https://orcid.org/0009-0009-3725-2248)
- Wei Yan (ORCID: https://orcid.org/0000-0001-9825-0689)
- Wen‐Cheng Liu (ORCID: https://orcid.org/0000-0002-5908-075X)
- Lin Cheng (ORCID: https://orcid.org/0000-0002-3688-9863)
- Heli Wang (ORCID: https://orcid.org/0000-0003-4207-0413)
- Zhuang Miao (ORCID: https://orcid.org/0000-0002-1004-6788)
- Sicen Liu (ORCID: https://orcid.org/0000-0001-6906-6233)
- Xiangdong Tang
- Hong Fu
- Tiantian Zhao
Institutions
- University of Electronic Science and Technology of China (CN)
- Sun Yat-sen University (CN)
- Chengdu Medical College (CN)
- Sichuan University (CN)
- West China Hospital of Sichuan University (CN)
- Huazhong University of Science and Technology (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-09-27
- DOI
- https://doi.org/10.1038/s41467-024-52601-1
- Citations
- 18
- Primary Topic
- Receptor Mechanisms and Signaling
- Type
- article
- Field-Weighted Citation Impact
- 4.21
Funders
- National Natural Science Foundation of China
- Ministry of Science and Technology of the People's Republic of China
- Sichuan University
- West China Hospital, Sichuan University