Marijuana receptor caught in the act

Marijuana has been used both recreationally and as a drug for centuries, has been banned in many countries for decades, and has recently been legalized in some U.S. states. But researchers haven’t been able to get a high-resolution look at the way its active component, Δ⁹-tetrahydrocannabinol (Δ⁹-THC), interacts with its principal protein receptor in the body, cannabinoid receptor 1 (CB₁).

CB₁ is a G protein-coupled receptor found mostly in central nervous system cell membranes. Last year, two groups managed to capture structures of CB₁ bound to inhibitors and in a “switched off” state. Activated receptors break down more easily when manipulated, so they are harder to crystallize and analyze structurally.

Now, one of the same groups—including Zhi-Jie Liu and Suwen Zhao of ShanghaiTech University, Laura M. Bohn of Scripps Research Institute Florida, and Alexandros Makriyannis of Northeastern University—has obtained high-resolution X-ray crystal structures of the receptor bound to two hydrocannabinol activating agents (Nature 2017, DOI: 10.1038/nature23272). The study, which reveals how agents such as Δ⁹-THC “turn on” CB₁, could help researchers design a new generation of safer therapeutics.

“CB₁ is a highly valued drug target for obesity, pain, fibrosis, and nonalcoholic steatohepatitis,” but current drugs that hit the receptor have serious side effects, Liu says.

The researchers obtained the new structures by designing and synthesizing two hydrocannabinols that resemble Δ⁹-THC but bind CB₁ with higher affinity, and by modifying four of the receptor’s amino acid residues to enhance its stability.

Compared with the inactivated receptor, activated CB₁ has a binding pocket 53% smaller in volume. It also has a twin toggle switch—two residues whose positions change to accommodate and promote agonist binding and receptor activation—and a larger surface area for binding G proteins.

Debra Kendall, an expert on cannabinoid receptor activation and signal transduction at the University of Connecticut School of Pharmacy, comments that she is “strongly positive” about the significance of the findings, noting that the determination of activated structures and their comparison with inhibitor-bound forms provide substantial detail on the mechanism of activation that could aid the design of novel CB₁-targeted drug candidates.