Research press release





今回、Zhi-Jie Liuたちの研究グループは、2種類のアゴニスト(合成THC誘導体)と複合体を形成したヒトCB1の結晶構造を解明した。その結果、アゴニストが結合したCB1の結晶構造における結合領域の容積が、アンタゴニストが結合したCB1より53%少なかったことが判明した。また、CB1は風船のような柔軟性を有しているが、このことが、多様な生理活性と心理活動がCB1によって調節される機構を説明するうえで役立つ可能性がある。さらに、CB1の結晶構造からは、CB1の活性に必須と考えられる「2つのトグルスイッチ」の存在も明らかになった。

The structures of the human cannabinoid receptor 1 (CB1) - the brain receptor that binds to Δ9-tetrahydrocannabinol (Δ9-THC), the main psychoactive ingredient in marijuana - in complex with two synthetic cannabinoids have been solved. The study, published online in Nature this week, reveals new details of the activation mechanism of the CB1 receptor and thus the mode of action of Δ9-THC and other psychoactive cannabinoids. The findings could have implications for physiological studies, drug discovery and human health.

Marijuana has been used for medicinal and recreational purposes across various cultures for more than 5,000 years. Its main psychoactive ingredient is the cannabinoid Δ9-THC, which exerts its effects by activating CB1. This receptor is activated by the brain’s own endocannabinoid system and is a therapeutic target for pain management, epilepsy and obesity. To understand how CB1 elicits its diverse physiological effects, knowledge of how it binds to agonists, such as D9-THC, is necessary; previous studies that have reported the structure of CB1 bound to antagonists have provided insights into only the inactive state of the receptor.

Zhi-Jie Liu and colleagues solve the crystal structures of human CB1 in complex with two agonists (synthetic THC derivatives). They find a 53% reduction in the volume of the binding region of the agonist-bound structure compared to the antagonist-bound structure. This balloon-like flexibility of CB1 may help to explain how it can modulate such diverse physiological and psychological activities. The structure also reveals a ‘twin toggle switch’ that seems to be essential for activating the receptor.

doi: 10.1038/nature23272

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