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.
<div data-thumb = "https://3c1703fe8d.site.internapcdn.net/newman/csz/news/tmb/2019/6-studyreveals.jpg" data-src = "https: //3c1703fe8d.site.internapcdn. net / newman / gfx / news / 2019/6-studyreveals.jpg "data-sub-html =" Type 2 cannabinoid receiver crystal. 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">