Understanding the diverse effects that cannabis has on the human body is imperative if we hope to take advantage of its medicinal properties to treat various disorders. As such, elucidating the molecular structure of the receptors that bind endocannabinoids is a critical step toward developing selective drugs that can differentiate between the two known receptors—CB1 and CB2—for these molecules. Since the structure of the CB1 receptor was resolved a few years ago, an international team of researchers led by scientists at the iHuman Institute within ShanghaiTech University has just published the crystal structure of the human type 2 cannabinoid receptor, CB2.

Type 2 cannabinoid receptor crystal. [Xiaoting Li et al./Cell]
Findings from the new study—published recently in Cell through an article titled “Crystal Structure of the Human Cannabinoid Receptor CB2”—should be helpful in the development of drugs against inflammatory, neurodegenerative, and other diseases. The study authors compared the newly discovered structure to that of the CB1 receptor, deeming the two receptors to be the “yin and yang” of the human endocannabinoid system.

The endocannabinoid pathway is a signaling system in the human body that regulates biological processes such as metabolism, pain sensation, neuronal activity, immune function, and so on. It has been shown that the cannabinoid receptors can be targeted to alleviate certain pathological conditions, including chronic pain.

While the CB1 receptors are mostly found in the nervous system and are responsible for psychoactive effects, the CB2 receptors are predominantly present in the immune system. Studies indicate that CB2 is a promising target for immunotherapy, as well as treating inflammatory and neuropathic pain, and neurodegenerative diseases. It has also been shown that molecules blocking CB2 can reduce tumor growth.

To effectively treat pathological conditions, drugs need to specifically target CB1 or CB2. However, the two receptors are very much alike. The amino acid sequences that encode them are 44% identical. Thus, developing selective medicine requires knowing the structure of both targets in great detail. Unlike CB1, the structure of CB2 had remained unknown.

To identify the shape of an individual molecule, researchers make a crystal from many such molecules. When arranged in this highly ordered way, the molecules can be exposed to x-rays, revealing their structure. The research team made a crystal from CB2 receptors bound to molecules blocking this receptor, which are potential drug candidates. That way, the x-ray analysis allowed the team to see both the structure of CB2 and how it connects to the blocking molecule or antagonist.

Conditions that can be affected by activating or inhibiting type 1 (CB1) or type 2 (CB2) cannabinoid receptors independently. [Xiaoting Li et al./Cell]
“We report the crystal structure of human CB2 in complex with a rationally designed antagonist, AM10257, at 2.8 Å resolution,” the authors wrote. 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.”

Because receptors are unstable proteins by nature, they needed to be modified using genetic engineering. This involved introducing mutations that make the protein stable without changing its structure or function. The investigators employed the use of computer software called CompoMug, which predicts mutations potentially useful for stabilizing receptor molecules. The mutations then need to be tested experimentally. In the current study, the CB2 receptor had five mutations prompted by CompoMug.

Interestingly, the research team concluded that substances activating one of the receptors can actually weaken or inhibit the other, and vice versa. This opens up a possibility not just for drugs that target exclusively one receptor, but those that affect both receptors, but in different ways.

“Every G protein-coupled receptor structure that is discovered has prospects for rational design of more efficient drugs,” surmised study investigator Petr Popov, PhD, assistant professor at the Moscow Institute of Physics and Technology. “Now that the structures of both cannabinoid receptors are known, we can design selective compounds targeting only one of the receptors, as well as agents with a desired polypharmacological profile targeting both receptors at once.”

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