Crystal Structure of the Human Cannabinoid Receptor CB2

Abstract

Graphical AbstractHighlights d Crystal structure of human CB2 in complex with antagonist AM10257 is determined d A high degree of conformational similarity with the agonistbound CB1 is uncovered d The yin-yang relationship of CB2 and CB1 will facilitate the design of selective drugs In BriefThe structure of the human cannabinoid receptor CB2 reveals how small molecules affect CB2 differently than CB1 and point to principles that could inform rational and selective drug design. SUMMARYThe cannabinoid receptor CB2 is predominately expressed in the immune system, and selective modulation of CB2 without the psychoactivity of CB1 has therapeutic potential in inflammatory, fibrotic, and neurodegenerative diseases. Here, we report the crystal structure of human CB2 in complex with a rationally designed antagonist, AM10257, at 2.8 Å resolution. The CB2-AM10257 structure reveals a distinctly different binding pose compared with CB1. However, the extracellular portion of the antagonist-bound CB2 shares a high degree of conformational similarity with the agonist-bound CB1, which led to the discovery of AM10257's unexpected opposing functional profile of CB2 antagonism versus CB1 agonism. Further structural analysis using mutagenesis studies and molecular docking revealed the molecular basis of their function and selectivity for CB2 and CB1. Additional analyses of our designed antagonist and agonist pairs provide important insight into the activation mechanism of CB2. The present findings should facilitate rational drug design toward precise modulation of the endocannabinoid system.

Detection and quantitation of synthetic cannabinoid receptor agonists in infused papers from prisons in a constantly evolving illicit market

“…Synthetic cannabinoid receptor agonists are a structurally diverse class of compounds that interact with human cannabinoid type 1 and type 2 G‐protein coupled receptors (GPCRs), CB 1 and CB 2. They vary widely in their potency and efficacy as a result of differences in their structural conformation, including chirality . Their diversity is due, in part, to the increased online availability of published research studies and patents describing their synthesis, in vitro potency and efficacy, and biological effects; the availability of precursor materials; increasing understanding of their structure–activity relationships by producers and suppliers; and as a response to the implementation of national and international legislation designed to control their production, prevalence, and use, and in particular, their use in prisons …”

“…Synthetic cannabinoid receptor agonists are a structurally diverse class of compounds that interact with human cannabinoid type 1 and type 2 G-protein coupled receptors (GPCRs), CB 1 and CB 2. [15][16][17][18][19] They vary widely in their potency and efficacy [20][21][22] as a result of differences in their structural conformation, including chirality. 23 Their diversity is due, in part, to the increased online availability of published research studies and patents describing their synthesis, in vitro potency and efficacy, and biological effects; the availability of precursor materials;…”

In vitro Phase I metabolism of indazole carboxamide synthetic cannabinoid MDMB‐CHMINACA via human liver microsome incubation and high‐resolution mass spectrometry

“…64 Recent discoveries regarding the CB 1 and CB 2 receptors have been published, including crystal structure determinations, molecular docking studies, and binding modes with natural and synthetic cannabinoids. [65][66][67] These studies are essential for understanding the way in which synthetic cannabinoids interact with these receptors, the effects that they induce, and the implications that this may have on consumers. More research is needed in the area of synthetic cannabinoid receptor binding, activity and metabolism to fully understand the mechanisms involved.…”

Structural insights into melatonin receptors

“…For example, cannabinoid, lysosphingolipid, and prostaglandin receptors belong to the α‐branch of class A GPCRs; leukotriene receptors to branches γ and δ; and free fatty acid receptors to the δ‐branch). Even within the α‐branch of class A, lysophosphatidic acid, sphingosine‐1‐phosphate, and cannabinoid receptors , which lack the canonical class A disulfide bridge between TM3 and ECL2, close off their binding sites mostly using their N terminus with minor ECL2 contributions. In contrast, prostaglandin receptors and rhodopsin display a tight lid formed from ECL2 with a β‐hairpin constrained to TM3 by the canonical class A disulfide bridge.…”