Ying Yang: The Second Cannabinoid Receptor

Structure of the CB1 receptor has already been resolved, now an international team of researchers led by ShanghaiTech University set out to do the same with CB2, and have published their findings in Cell which should be helpful in development of drugs against neurodegenerative, inflammatory, and other diseases.

This study compares newly discovered structures to those of the CB1 receptor, and deems the two receptors to be the Yin and Yang of the human endocannabinoid system, which is a signalling system that regulates biological processes such as pain, immune function, metabolism, and neuronal activities among others.

CB2 receptors are found in the immune system, and CB1 receptors responsible for psychoactive effects are found in the nervous system. CB2 studies indicate it to be a promising target for immunotherapy, treating inflammatory pain, neurodegenerative pain, neurodegenerative diseases, and molecule blocking CB2 have been shown to reduce tumor growth.

To treat pathological conditions effectively drugs must target CB1/CB2 specifically. Amino acid sequences that encode them are 44% identical making the receptors very much alike, and developing selective medicines requires knowledge of both target structures in detail, which until now only CB1 was known.

A crystal was made from CB2 receptors bound to blocking molecules to identify the shape of any such molecule, then X-ray analysis allowed the team to see the CB2 structure and how it connects to blocking molecules or antagonists.

The team reports “The crystal structure of human CB2 in complex with rationally designed antagonist AM10257 at 2.8 A resolution reveals distinctly different binding pose than CB1, but the extracellular portion of the antagonist bound CB2 shares high degree of conformational similarity. Analysis revealed AM10257’s opposing functional profile of CB2 antagonism vs CB1, further structural analysis using mutagenesis studies and molecular docking revealed molecular basis of their function and selectivity for the two receptors. Analyses of the designed antagonist and agonist pairs provided insight into the activation mechanism of CB2.”

Unstable proteins by natural the receptors needed to be genetically modified which involved introducing mutations to make the protein sable without changes its function or structure. CompoMug computer software was used to predict 5 mutations potentially useful for stabilizing receptor molecules to be tested experimentally.

The international team concluded substances activating one of the receptors can weaken or inhibit the other and vice versa, opening possibilities for drugs to target both receptors exclusively or together but in different ways.

Petr Popov, PhD surmised “Every G protein coupled receptor discovered has prospect for rational design of new and efficient drugs. Now that both cannabinoid structure receptors are known selective compounds can be design to target one of the receptors as well as agents with desired polypharmacological profiles to target both receptors together.”