大麻素受体CB1别构调节机制的结构生物学研究

大麻素受体CB1是人体中枢神经系统中表达量最高和分布最广的GPCR，大麻作为娱乐和药物使用已经有几千年的历史，其主要有效成分——四氢大麻酚（THC）主要作用于CB1。CB1是治疗老年痴呆、抑郁症、疼痛、炎症、肥胖及药物滥用等的重要靶点。CB1的三维结构信息对内源性大麻素系统的功能机制研究及新药研发极其重要。我们在过去的两年中成功解析了CB1受体分别与正构调节配体拮抗剂和激动剂复合物的三维精细结构。相对于正构调节配体，别构调节配体具有位点选择性和作用多样性等优势，然而，目前对CB1受体的别构调节配体的结合方式和作用机理还不是很清楚。本项目将以晶体学为主，冷冻电镜相辅相成的方法，解析CB1受体与不同别构调节配体复合物的三维精细结构。结合核磁共振及细胞水平的功能检测，最终从分子及细胞水平阐述大麻素受体CB1的别构调节机制，获得具有偏向选择性的新型别构调节配体。

Cannabinoid receptor 1 (CB1) is the principal target of ∆9-tetrahydrocannabinol (THC), a psychoactive chemical from Cannabis sativa with a wide range of therapeutic applications and a long history of recreational use. CB1 is the most highly expressed GPCR in the human brain and is expressed throughout the body. CB1 is a promise therapeutic target for treatment of a wide range of disorders, including obesity, pain, inflammation, multiple sclerosis and neurodegenerative disorders. The 3D structure information will enhance our understanding of the molecular basis for the physiological functions of CB1 and provide new opportunities for the design of the next-generation CB1-targeting pharmaceuticals. We have solved the structures of CB1 in complex with antagonist and agonist, respectively. Recent studies show that allosteric modulators hold potential to develop subtype-specific and pathway-specific therapeutics compared with orthosteric ligands. However, the binding modes and molecular mechanism of CB1 allosteric modulation are still unknown. In this study, we will solve the high-resolution crystal structures of CB1 in complex with different allosteric modulators, and also perform the nuclear magnetic resonance (NMR) and pharmacology studies, to improve our understanding on the molecular basis of CB1 allosteric modulation mechanism and provide insights on the design of next-generation CB1 allosteric modulators. These achievements will help to unravel the mechanistic basis of GPCR allosteric modulation at the molecular level and improve the strategic design of small molecules for lead identification and optimization targeting allosteric binding sites.