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The study reveals the structure of the second cannabinoid human receptor



The study reveals the structure of the 2nd human cannabinoid receptor

Human cannabinoid receptors respond to compounds found in cannabis. Credit: @ tsarcyanide / MIPT

A Chinese research team has joined forces with Russian and American biologists to obtain the crystalline structure of the human cannabinoid type 2 receptor. Their results could lead to medications against inflammatory, neurodegenerative and other diseases. The authors of the newspaper, published in Cell, compares the recently discovered structure with that of the cannabinoid type 1 receptor, considering that the two receptors are the yin and the yang of the human endocannabinoid system.

Drugs rely on knowing the receptor structure

The two cannabinoid receptors, CB1 and CB2, belong to the so-called endocannabinoid system. This refers to a system of signaling in the human body that regulates biological processes such as metabolism, pain sensation, neuronal activity, immune function and others. It has been found that cannabinoid receptors may be subject to relief for certain pathological conditions, including chronic pain.

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

To effectively deal with pathological conditions, drugs should specifically target CB1 or CB2. However, the two receivers are very similar. The amino acid sequences that encode them are 44% identical. Therefore, developing a selective medicine requires the structure of the two objectives to be in great detail. Unlike CB1, the structure of the CB2 has remained unknown until now.

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The study reveals the structure of the 2nd human cannabinoid receptor

Cannabinoid receptor crystal type 2. Credit: Xiaoting Li et al./Cell

The X-ray crystal CB reveals its structure

To identify the shape of an individual molecule, the researchers make a crystal of many molecules of this type. When it is arranged in this highly ordered way, molecules can be exposed to X-rays, revealing their structure.

The team made a crystal (Figure 1) of CB2 receptors linked to molecules that block this receptor, which are possible candidates for medications. In this way, the X-ray analysis allowed the team to see both the CB2 structure and its connection to the blocking or antagonist molecule.

However, the receptors are proteins unstable by nature. To study them, they need to be modified by means of genetic engineering. This implies the introduction of mutations that make the protein stable without changing its structure or function.

CompoMug is a software package that provides potentially useful mutations for the stabilization of the receiving molecules. Mutations have to be tested experimentally. This software was developed by two researchers from the Physics and Technology Institute of Moscow and the University of Southern California: visiting Professor MIPT Vsevolod Katritch and Petr Popov of the Structural Biology Laboratory of G-coupled receptors.

<div data-thumb = "https://3c1703fe8d.site.internapcdn.net/newman/csz/news/tmb/2019/7-studyreveals.jpg" data-src = "https: //3c1703fe8d.site.internapcdn. net / newman / gfx / news / 2019/7-studyreveals.jpg "data-sub-html =" Conditions that may be affected by the activation or inhibition of cannabinoid receptors type 1 (CB1) or type 2 (CB2) independently. Li et al./Cell">

The study reveals the structure of the 2nd human cannabinoid receptor

Conditions that may be affected by the activation or inhibition of cannabinoid receptors type 1 (CB1) or type 2 (CB2) independently. Credit: Xiaoting Li et al./Cell

In the study, the CB2 receptor had five mutations driven by CompoMug.

The discovery of the receptor structure allows more intelligent drugs

The researchers contrasted the CB2 structure with that of CB1. They have concluded that the substances that activate one of the receptors can weaken or inhibit the other, and vice versa. This opens up a possibility not only for drugs that are used exclusively for a recipient, but also affect both receptors, but in different ways. Figure 2 shows the therapeutic implications.

"Every G-protein-coupled receptor structure that is discovered has prospects for rational drug design more efficient," explains study co-author Petr Popov. "Now that we know the structures of the two cannabinoid receptors, we can design selective compounds destined only to one of the receptors, as well as agents with a desired polypharmacological profile that targets both recipients at the same time."


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More information:
Xiaoting Li et al, Crystal structure of the human cannabinoid receptor CB2, Cell (2019). DOI: 10.1016 / j.cell.2018.12.011

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Institute of Physics and Technology of Moscow

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The study reveals the structure of the second human cannabinoid receptor (2019, February 28)
recovered on February 28, 2019
https://medicalxpress.com/news/2019-02-reveals-human-cannabinoid-receptor.html

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