Crystal structures of agonist-bound human cannabinoid receptor CB1，Nature 27 July 2017: Vol. 547, Issue 7664, pp. 468-471

Nature, 27 July 2017: Vol. 547, Issue 7664, pp. 468-471, DOI: doi:10.1038/nature23272

Crystal structures of agonist-bound human cannabinoid receptor CB1

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

Abstract

The cannabinoid receptor 1 (CB1) is the principal target of the psychoactive constituent of marijuana, the partial agonist Δ9-tetrahydrocannabinol (Δ9-THC). Here we report two agonist-bound crystal structures of human CB1 in complex with a tetrahydrocannabinol (AM11542) and a hexahydrocannabinol (AM841) at 2.80 angstrom and 2.95 angstrom resolution, respectively. The two CB1-agonist complexes reveal important conformational changes in the overall structure, relative to the antagonist-bound state, 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 numbering) 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.

文章链接：http://www.nature.com/articles/nature23272