Crystal structures of agonist-bound human cannabinoid receptor CB1

• Published in: Nature (London) Vol. 547; no. 7664; pp. 468 - 471
• Main Authors: Hua, Tian, Vemuri, Kiran, Nikas, Spyros P., Laprairie, Robert B., 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
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 27-07-2017; Nature Publishing Group
• Subjects: 101/58; 119/118; 14/19; 631/154/309/2420; 631/535/1266; 631/80/86; 82/80; 82/83; 96/31; Analysis; Cannabinoids; Crystal structure; Humanities and Social Sciences; letter; Ligand binding (Biochemistry); multidisciplinary; Science; United States
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature23272

Crystal structures of the human cannabinoid receptor 1 (CB
1
) 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.
Cannabinoid receptor structure
The human cannabinoid receptor 1 (CB
1
) is the main target of the plant cannabinoid Δ
9
-tetrahydrocannbinol (Δ
9
-THC), the key psychoactive compound in
Cannabis sativa
. CB
1
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 CB
1
activated by two potent Δ
9
-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 (CB
1
) is the principal target of the psychoactive constituent of marijuana, the partial agonist Δ
9
-tetrahydrocannabinol (Δ
9
-THC)
1
. Here we report two agonist-bound crystal structures of human CB
1
in complex with a tetrahydrocannabinol (AM11542) and a hexahydrocannabinol (AM841) at 2.80 Å and 2.95 Å resolution, respectively. The two CB
1
–agonist complexes reveal important conformational changes in the overall structure, relative to the antagonist-bound state
2
, 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 Phe200
3.36
and Trp356
6.48
(superscripts denote Ballesteros–Weinstein numbering
3
) is experimentally observed and appears to be essential for receptor activation. The structures reveal important insights into the activation mechanism of CB
1
and provide a molecular basis for predicting the binding modes of Δ
9
-THC, and endogenous and synthetic cannabinoids. The plasticity of the binding pocket of CB
1
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.