Gloriam David, Thorsen Thor, Kulkarni Yashraj, Sykes David, Bøggild Andreas, Drace Taner, Hompluem Pattarin, Iliopoulos-Tsoutsouvas Christos, Nikas Spyros, Daver Henrik, Makriyannis Alexandros, Nissen Poul, Gajhede Michael, Veprintsev Dmitry, Boesen Thomas, Kastrup Jette
University of Copenhagen.
University of Nottingham.
Res Sq. 2024 May 21:rs.3.rs-4277209. doi: 10.21203/rs.3.rs-4277209/v1.
Δ-tetrahydrocannabinol (THC) is the principal psychoactive compound derived from the cannabis plant Cannabis sativa and approved for emetic conditions, appetite stimulation and sleep apnea relief. THC's psychoactive actions are mediated primarily by the cannabinoid receptor CB. Here, we determine the cryo-EM structure of HU210, a THC analog and widely used tool compound, bound to CB and its primary transducer, G. We leverage this structure for docking and 1,000 ns molecular dynamics simulations of THC and 10 structural analogs delineating their spatiotemporal interactions at the molecular level. Furthermore, we pharmacologically profile their recruitment of G and β-arrestins and reversibility of binding from an active complex. By combining detailed CB structural information with molecular models and signaling data we uncover the differential spatiotemporal interactions these ligands make to receptors governing potency, efficacy, bias and kinetics. This may help explain the actions of abused substances, advance fundamental receptor activation studies and design better medicines.
Δ-四氢大麻酚（THC）是从大麻植物大麻中提取的主要精神活性化合物，已被批准用于催吐、刺激食欲和缓解睡眠呼吸暂停。THC的精神活性作用主要由大麻素受体CB介导。在此，我们确定了HU210（一种THC类似物，也是广泛使用的工具化合物）与CB及其主要转导蛋白G结合的冷冻电镜结构。我们利用该结构对THC和10种结构类似物进行对接和1000纳秒的分子动力学模拟，在分子水平上描绘它们的时空相互作用。此外，我们从药理学角度分析了它们对G蛋白和β-抑制蛋白的募集以及从活性复合物中结合的可逆性。通过将详细的CB结构信息与分子模型和信号数据相结合，我们揭示了这些配体与受体之间不同的时空相互作用，这些相互作用决定了效力、功效、偏向性和动力学。这可能有助于解释滥用物质的作用，推进基础受体激活研究，并设计出更好的药物。
