Recently, Professor Shao Zhenhua’s team from the State Key Laboratory of Biotherapy and the Nephropathy Laboratory of WCH released the research paper--Structure of an Allosteric Modulator Bound to the CB1 Cannabinoid Receptor on Nature Chemical Biology (IF:12.15), an influential international magazine.  

This study has been jointly completed by Professor Shao Zhenhua’s team and Prof. Danile Rosenbaum from Southwestern Medical Center, the University of Texas. Research Fellow Shao Zhenhua is the first author, Associate Research Fellow Yan Wei from the State Key Laboratory of Biotherapy is the second author, and the State Key Laboratory of Biotherapy and the Nephropathy Laboratory of WCH are the first institutes.

The cannabinoid receptor CB1, belongs to the Class A GPCRs, is highly expressed in the human center nervous system, and the cannabinoids-based drugs could adjust the physiological reaction by activating such kind of receptors. CB1 receptor has been all the time the therapeutic targets for such diseases as ache, anxiety and epilepsy; and their agonist and antagonist ligands could target the orthosteric pocket in CB1 receptor, resulting in opening and closing of the signaling pathway respectively. In addition to the orthosteric pocket (agonist and antagonist), their allosteric modulators not only affect the combination with the cannabinoids agonist, but also represents the signal transduction. The molecular mechanism of allosteric modulators would gain a better understanding of the complicated mechanism of the GPCR signal transduction. 

By solving the three-dimensional complex structure of CB1 receptors with allosteric modulators, a brand-new allosteric site in the CB1 receptor was found,  which is different from the previous GPCR’s allosteric sites. The variability and non-conservative properties of the allosteric sites of the GPCR family provided a new strategy for designing selective potential drugs, especially among the multiple subtypes of receptors. On the one hand, this paper could help us understand the signal transduction mechanism of CB1 receptors more systematically; on the other hand, the synergistic effect (possibly with low side effect) of allosteric modulators with agonists provides a new strategy in the development of new medicines for CB1 receptors.

The link of the article：https://www.nature.com/articles/s41589-019-0387-2