Structure and Function of CB2 Receptor

项目总结 这个多PI R01研究方案的中心焦点是人类的结构-功能表征 大麻素受体2(CB2)，内源性大麻素系统的关键蛋白质成分。我们的目标是发展 对CB2功能的结构基础有基本的理解，最终的翻译目标是 建立健全的基于结构的药物设计(SBDD)计划。ECS是一个复杂的脂质网络 配体、受体和代谢酶参与一系列重要的生理过程。 已经有了重要的暗示，靶向CB2作为一种治疗手段可能是有用的 炎症、疼痛、神经紊乱和成瘾。与其他G蛋白偶联受体一样 (GPCRs)，CB2可以在不同的配体上表现出优先的信号事件。此功能 选择性提供了改进治疗方法、改善有益属性的机会，以及 减少副作用责任。这项研究将为设计和开发提供结构基础 药理上不同的CB2选择性化合物作为有用的生物探针和/或线索 治疗学的未来发展。为了加强我们获得优质晶体结构的努力，我们将 使用精心设计的具有高亲和力和选择性的CB2配体，这些配体还能够 在受体结合域或其附近的紧密结合(S)与其形成结晶的能力相结合 配体-受体复合体。本研究有三个具体目标：(1)设计和合成新型不可逆性材料 代表CB2选择性化合物的关键类别的配体，具有不同的功能图谱。(2)广泛性 对新合成的配体进行表征，以便对化合物进行药理鉴定 不同的图谱，包括部分激动剂、反向激动剂、中性拮抗剂和变构 调制器。候选结晶和它们的化学衍生物也将被表征为它们的 使用功能分析的可逆结合性质。(3)对CB2配体结合有一个清晰的认识 通过确定几个受体-配体络合物的三维结构来确定其位置。为了实现这些目标， 将解决几个晶体结构，以更好地理解分子识别、信号传递和协助 新化合物的设计，然后可以作为下一代先导和药物的原型 候选人。

PROJECT SUMMARY The central focus of this Multi-PI R01 research proposal is the structure-function characterization of the human cannabinoid receptor 2 (CB2), a key protein component of the endocannabinoid system. We aim to develop a fundamental understanding of the structural basis of CB2 function, with the ultimate translational goal of establishing a robust structure-based drug design (SBDD) program. The ECS is a complex network of lipid ligands, receptors, and metabolic enzymes involved in a wide range of important physiological processes. There have been important implications that targeting CB2 may be useful as a means for treating inflammation, pain, neurological disorders and addiction. As with other G protein-coupled receptors (GPCRs), CB2 can exhibit preferential signaling events in response to different ligands. This functional selectivity offers the opportunity to refine therapeutic approaches, to improve beneficial properties, and reduce side effect liability. The study will provide the structural basis for the design and development of pharmacologically distinct CB2-selective compounds as useful biological probes and/or leads for the future development of therapeutics. To enhance our effort in obtaining high quality crystal structures, we shall use carefully designed ligands with high affinities and selectivities for CB2, and which are also capable of tight attachment at or near the receptor’s binding domain(s) coupled with their abilities to form crystallizable ligand-receptor complexes. The study has three specific aims: (1) Design and synthesize novel irreversible ligands representing key classes of CB2 selective compounds with distinct functional profiles. (2) Extensive characterization of the newly synthesized ligands in order to identify compounds with pharmacologically diverse profiles, including the partial agonists, inverse agonists, neutral antagonists and allosteric modulators. The crystallization candidates and their chemical derivatives will also be characterized for their reversible binding nature using functional assays. (3) Develop a clear understanding of CB2 ligand binding sites by determining the 3-D structures of the several receptor-ligand complexes. Towards these goals, several crystal structures will be solved to better understand molecular recognition, signaling, and to assist in the design of novel compounds that could then serve as prototypes for later generation leads and drug candidates.