Cryo-EM structure of small-molecule agonist bound delta opioid receptor-Gi complex enables discovery of biased compound

Lin Cheng, Zhuang Miao, Sicen Liu, Zhe Li, Hong Fu, Chanjuan Xu, Shilong Hu, Chang Zhao, Yuxuan Liu, Tiantian Zhao, Wencheng Liu, Heli Wang, Runduo Liu, Wei Yan, Xiangdong Tang, Jianfeng Liu (), Zhenhua Shao () and Bowen Ke ()
Additional contact information
Lin Cheng: Sichuan University
Zhuang Miao: Sichuan University
Sicen Liu: Sichuan University
Zhe Li: Sun Yat-sen University
Hong Fu: Sichuan University
Chanjuan Xu: Huazhong University of Science and Technology
Shilong Hu: Sichuan University
Chang Zhao: Sichuan University
Yuxuan Liu: Huazhong University of Science and Technology
Tiantian Zhao: Sichuan University
Wencheng Liu: Sichuan University
Heli Wang: Sichuan University
Runduo Liu: Sun Yat-sen University
Wei Yan: Sichuan University
Xiangdong Tang: Sichuan University
Jianfeng Liu: Huazhong University of Science and Technology
Zhenhua Shao: Sichuan University
Bowen Ke: Sichuan University

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: Abstract 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-Gi 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.

Date: 2024
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DOI: 10.1038/s41467-024-52601-1

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