Highest-resolution model to date of brain receptor behind marijuana's high

November 16, 2016

Science Daily/UT Southwestern Medical Center

Researchers at UT Southwestern Medical Center report the most detailed 3-D structure to date of the brain receptor that binds and responds to the chemical at the root of marijuana's high.

Their high-resolution structure of the human cannabinoid receptor 1 (CB1) and its binding site for the chemical tetrahydrocannabinol (THC) should lead to a better understanding of how marijuana affects the brain. The research also could aid discovery of new treatments for conditions that target the receptor, said Dr. Daniel Rosenbaum, Assistant Professor of Biophysics and Biochemistry at UT Southwestern.

"What is most exciting from a therapeutic standpoint is that the same receptor pocket that binds THC also binds cannabinoid inhibitors that have been studied as possible treatments for conditions such as obesity," said Dr. Rosenbaum, senior author of the study published online by Nature. "The structure is an important step toward explaining how cannabinoids initiate signals in the brain that affect the release of neurotransmitters that relay messages between the brain's neurons," Dr. Rosenbaum said. "This 3-D structure provides high-resolution details of the binding pocket in the CB1 receptor, where plant cannabinoids like THC, cannabinoids made in the body, and synthetic cannabinoid inhibitors all work to modulate receptor function and physiology." He said the CB1 receptor is the target for cannabinoid inhibitor drugs now under study as possible treatments for epilepsy, pain control, obesity, and other conditions.

In a competing study released last month by the journal Cell, a U.S.-Chinese team of researchers reported a 3-D structure of the CB1 receptor at a resolution of 2.8 angstroms. The UT Southwestern study reports a higher resolution of 2.6 angstroms. (One angstrom is equivalent to one hundred-millionth of a centimeter.) The higher the resolution, the finer the details of the relationship between atoms of the protein.

"The resolution is very important. Our structure shows a different and better resolved structure at the important binding pocket that is of interest to scientists involved in drug development," Dr. Rosenbaum said. "Overall, these two structures are complementary, but we believe our structure may provide a better framework for understanding how cannabinoids and inhibitors bind to the receptor."

The Cell study examined the CB1 receptor bound to a synthetic chemical created to stabilize the receptor. In contrast, the UT Southwestern research team successfully imaged the receptor bound to the drug taranabant, which was tested as a possible anti-obesity treatment in clinical trials. Those trials ended due to side effects such as anxiety and depression, Dr. Rosenbaum said.

CB1 and the related CB2, which still lacks a high-resolution structural solution, are both members of the human G protein-coupled receptor family. Members of that receptor family control signaling pathways involving hormones, neurotransmitters, and sensory stimuli such as light and odors.

The team's success depended on overcoming the receptor protein's resistance to crystallization, which is required for the diffraction measurements used in X-ray crystallography. The researchers also conducted computer simulations of how THC might bind to the CB1 receptor, he said.

The next step is to obtain structures of CB1 actually bound to THC, he said.

https://www.sciencedaily.com/releases/2016/11/161116131935.htm

First atomic-level image of the human 'marijuana receptor' unveiled

October 20, 2016

Science Daily/Scripps Research Institute

In a discovery that advances the understanding of how marijuana works in the human body, an international group of scientists, including those from the Florida campus of The Scripps Research Institute (TSRI), have for the first time created a three-dimensional atomic-level image of the molecular structure activated by tetrahydrocannabinol (THC), the active chemical in marijuana.

The new insights into the human cannabinoid receptor 1 (CB1) will provide an essential tool for understanding why some molecules related to THC have unexpectedly complex and sometimes harmful effects. The findings also have the potential to guide drug design for pain, inflammation, obesity, fibrosis and other indications.

The new study, published by the journal Cell, was led by a quartet of scientists: TSRI's Laura Bohn, Northeastern University's Alexandros Makriyannis, Shanghai Tech University's Zhi-Jie Liu and Raymond C. Stevens (also of the University of Southern California).

At the beginning of the study, the team struggled to produce a crystal form -- needed to obtain data to recreate the high-resolution structure -- of the receptor bound with AM6538, a stabilizing a molecule that blocks the receptor's action.

"The CB1 receptor proved as challenging for crystallization as it did for understanding its functional regulation and signaling," said Bohn, who is a professor in TSRI's Department of Molecular Therapeutics.

When the scientists succeeded in crystalizing the receptor and collecting the data, the structure of the cannabinoid receptor complex revealed an expansive and complicated binding pocket network consisting of multiple sub-pockets and channels to various regions of the receptor.

Cannabinoid receptors are part of a large class of receptors known as G protein-coupled receptors (GPCR), which account for about 40 percent of all prescription pharmaceuticals on the market, and play key roles in many physiological functions. When an outside substance binds to a GPCR, it activates a G protein inside the cell to release components and create a specific cellular response.

AM6538, is an antagonist/inverse agonist that binds tightly to the receptor; it has a long half-life, making it potentially useful as a treatment of addiction disorders.

"As marijuana continues to become more common in society, it is critical that we understand how it works in the human body," said Liu, who is professor and deputy director of the iHuman Institute of Shanghai Tech and is also affiliated with the Chinese Academy of Sciences.

https://www.sciencedaily.com/releases/2016/10/161020223928.htm