Crystal structures of agonist-bound human cannabinoid receptor CB1

Autor: Jo-Hao Ho, Spyros P. Nikas, Zhi-Jie Liu, Tian Hua, Yiran Wu, Anisha Korde, Haiguang Liu, Kiran Vemuri, Mengchen Pu, Gye Won Han, Kang Ding, Raymond C. Stevens, Alexandros Makriyannis, Shan Jiang, Xuanxuan Li, Laura M. Bohn, Michael A. Hanson, Suwen Zhao, Robert B. Laprairie, Lu Qu
Rok vydání: 2017
Předmět:
Zdroj: Nature. 547:468-471
ISSN: 1476-4687
0028-0836
DOI: 10.1038/nature23272
Popis: Crystal structures of the human cannabinoid receptor 1 (CB1) bound to the agonists AM11542 and AM841 reveal notable structural rearrangements upon receptor activation, and this flexibility may be a common feature among other G-protein-coupled receptors. The human cannabinoid receptor 1 (CB1) is the main target of the plant cannabinoid Δ9-tetrahydrocannbinol (Δ9-THC), the key psychoactive compound in Cannabis sativa. CB1 is activated by endocannabinoids and is a therapeutic target for pain management, epilepsy and obesity, among others, although an active receptor structure is still lacking. Here, Zhi-Jie Liu and colleagues report the crystal structure of CB1 activated by two potent Δ9-THC derivatives, AM11542 and AM841. Both of these agonists have a gem-dimethyl group on their alkyl chain which leads to significant enhancement in their potency and efficacy. Receptor activation involves large-scale structural rearrangements on both extracellular and cytoplasmic sides and a significant reduction in the size of the binding pocket. These conformational changes involve a novel molecular 'twin toggle switch', the synergistic movement of two key residues during activation, which the authors suggest may be common to other G-protein-coupled receptors. The cannabinoid receptor 1 (CB1) is the principal target of the psychoactive constituent of marijuana, the partial agonist Δ9-tetrahydrocannabinol (Δ9-THC)1. Here we report two agonist-bound crystal structures of human CB1 in complex with a tetrahydrocannabinol (AM11542) and a hexahydrocannabinol (AM841) at 2.80 A and 2.95 A resolution, respectively. 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. In addition, a ‘twin toggle switch’ of Phe2003.36 and Trp3566.48 (superscripts denote Ballesteros–Weinstein numbering3) is experimentally observed and appears 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.
Databáze: OpenAIRE
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