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Cannabinoid receptor structure revealed

The molecular structure of CB1 (yellow ribbon) bound with AM6538 (orange stick structure). THC, the active ingredient in marijuana, is shown as well (yellow stick structures).Yekaterina Kadyshevskaya, Stevens Laboratory, University of Southern California

The Cannabis sativa plant, also known as marijuana, contains compounds called cannabinoids, which can act on the brain to affect mood or consciousness. Tetrahydrocannabinol, or THC, is perhaps the best known of these compounds. Some evidence suggests that cannabinoids might help to treat certain health conditions. Possible uses include pain, inflammation, epilepsy, nerve cell diseases, and substance use disorders. However, some cannabinoids can cause side effects, such as dizziness, hallucinations, and paranoia. Some synthetic cannabinoids, such as K2 or Spice, can produce severe and even deadly reactions.

Cannabinoids exert their primary effects in the brain by binding the human cannabinoid (CB₁) receptor. Determining the detailed 3-D structure of this receptor at a fine level is important for potential drug development, as it reveals key details about how the receptor and drugs might interact. An international group of researchers set out to determine the structure of the CB₁ receptor. Their work was funded in part by NIH’s National Institute on Drug Abuse (NIDA). The study appeared on October 20, 2016, in Cell.

The researchers synthesized a chemical called AM6538 that they designed to inactivate and help crystallize the CB₁ receptor. They slightly modified CB₁ as well to optimize it for crystallization. They then computed the 3-D structure of the CB₁-AM6538 complex using X-ray crystallography, in which the angles and intensities of X-rays that bounce off a crystal structure are used to determine molecular shape.

The crystal structure revealed that the CB₁ receptor has a complicated binding pocket with multiple subpockets. Based on prior findings, the scientists were able to predict how other cannabinoids would fit into the receptor. The model revealed insights into how long each cannabinoid might bind to the CB₁ receptor and how each might cause slightly different structural changes to the receptor. These findings provide clues to the mechanisms by which different cannabinoids can exert somewhat differing effects.

“Cannabinoids can produce very different outcomes, depending on how they bind to the CB₁ receptor,” says NIDA Director Dr. Nora D. Volkow. “Understanding how these chemicals bind to the CB₁ receptor will help guide the design of new medications and provide insight into the therapeutic promise of the body’s cannabinoid system.”

“This complex structure will allow chemists to design diverse compounds that specifically target portions of the receptor to produce desired effects,” says co-author Dr. Alexandros Makriyannis of Northeastern University.