Crystal structures of agonist-bound human cannabinoid receptor CB₁

Area of Science:

• Structural biology
• Neuroscience
• Pharmacology

Background:

• Cannabinoid receptor 1 (CB₁) is the primary target of Δ⁹-tetrahydrocannabinol (Δ⁹-THC), the main psychoactive component of marijuana.
• Understanding CB₁ receptor activation is crucial for developing targeted therapeutics.

Purpose of the Study:

• To determine the crystal structures of human CB₁ in complex with agonist-bound ligands.
• To elucidate the conformational changes and molecular mechanisms underlying CB₁ receptor activation.

Main Methods:

• X-ray crystallography of human CB₁ receptor with tetrahydrocannabinol (AM11542) and hexahydrocannabinol (AM841) agonists.
• Comparative structural analysis with antagonist-bound states.

Main Results:

• Revealed significant conformational changes in CB₁ upon agonist binding, including a 53% reduction in ligand-binding pocket volume.
• Identified a 'twin toggle switch' mechanism involving Phe200 and Trp356, crucial for receptor activation.
• Observed an increased surface area in the G protein-binding region.

Conclusions:

• The study provides atomic-level insights into the activation mechanism of the CB₁ receptor.
• These structures offer a molecular framework for predicting the binding of various cannabinoids.
• Findings will guide the design of novel ligands with specific pharmacological profiles for CB₁-related conditions.