近日，上海科技大学大学刘志杰团队的最新研究提出了激动剂结合的人大麻素受体CB₁的晶体结构。该研究于2025年8月27日发表于国际一流学术期刊《自然》杂志上。

在这里，小组报道了人类CB₁与四氢大麻酚（AM11542）和六氢大麻酚（AM841）配合物的两种激动剂结合晶体结构。与拮抗剂结合状态相比，这两种CB₁激动剂复合物在整体结构上显示出重要的构象变化，包括配体结合袋的体积减少53%，G蛋白结合区的表面积增加。

此外，通过实验观察到Phe2003.36和Trp3566.48（上标表示Ballesteros-Weinstein编号）的双拨动开关，这似乎是受体激活所必需的。这些结构揭示了CB₁激活机制的重要见解，并为预测Δ9-THC、内源性和合成大麻素的结合模式提供了分子基础。CB₁结合袋的可塑性似乎是某些a类G蛋白偶联受体的共同特征。这些发现应该启发设计具有不同药理性质的化学多样化配体。

据悉，大麻素受体1（CB₁）是部分激动剂Δ9-四氢大麻酚（Δ9-THC）的主要靶点，部分激动剂是大麻的精神活性成分。

附：英文原文

Title: Crystal structures of agonist-bound human cannabinoid receptor CB1

Author: Hua, Tian, Vemuri, Kiran, Nikas, Spyros P., Wu, Yiran, Qu, Lu, Pu, Mengchen, Korde, Anisha, Jiang, Shan, Ho, Jo-Hao, Han, Gye Won, Ding, Kang, Li, Xuanxuan, Liu, Haiguang, Hanson, Michael A., Zhao, Suwen, Bohn, Laura M., Makriyannis, Alexandros, Stevens, Raymond C., Liu, Zhi-Jie

Issue&Volume: 2025-08-27

Abstract: Cannabinoid receptor 1 (CB1) is the primary target of the partial agonist Δ9-tetrahydrocannabinol (Δ9-THC), the psychoactive constituent of marijuana1. Here we report two agonist-bound crystal structures of human CB1 in complex with a tetrahydrocannabinol (AM11542) and a hexahydrocannabinol (AM841). The two CB1–agonist complexes reveal important conformational changes in the overall structure relative to the antagonist-bound state2, including a 53% reduction in the volume of the ligand-binding pocket and an increase in the surface area of the G protein-binding region. Furthermore, a twin toggle switch of Phe2003.36 and Trp3566.48 (where the superscripts denote Ballesteros–Weinstein numbering3) is experimentally observed and seems to be essential for receptor activation. The structures reveal important insights into the activation mechanism of CB1 and provide a molecular basis for predicting the binding modes of Δ9-THC, and endogenous and synthetic cannabinoids. The plasticity of the binding pocket of CB1 seems to be a common feature among certain class A G protein-coupled receptors. These findings should inspire the design of chemically diverse ligands with distinct pharmacological properties.

DOI: 10.1038/s41586-025-09454-5

Source: https://www.nature.com/articles/s41586-025-09454-5