Structure and Function of CB2 Receptor

项目摘要 这项多PI R 01研究提案的中心焦点是人类的结构-功能表征。 大麻素受体2（CB 2）是内源性大麻素系统的关键蛋白质组分。我们的目标是开发 对CB 2功能的结构基础有基本的了解，最终的翻译目标是 基于结构的药物设计（SBDD）。ECS是一个复杂的脂质网络， 配体、受体和代谢酶参与广泛的重要生理过程。 有重要的意义，靶向CB 2可能是有用的，作为一种手段，治疗 炎症、疼痛、神经障碍和成瘾。与其他G蛋白偶联受体一样 在GPCR中，CB 2可以响应于不同的配体表现出优先的信号传导事件。该功能 选择性提供了改进治疗方法，改善有益特性， 减少副作用责任。本研究将为设计和开发 选择性CB 2-选择性化合物作为生物学方法的有用的生物探针和/或先导物 治疗学的未来发展。为了加强我们在获得高质量晶体结构方面的努力，我们将 使用精心设计的对CB 2具有高亲和力和选择性的配体，并且其还能够 在受体结合结构域处或附近的紧密附着与它们形成可结晶的 配体-受体复合物。本研究的具体目标有三：（1）设计合成新型的不可逆 代表具有不同功能特征的关键类别的CB 2选择性化合物的配体。(2)广泛 新合成的配体的表征，以确定化合物与 不同的概况，包括部分激动剂，反向激动剂，中性拮抗剂和变构 调制器。结晶候选物和它们的化学衍生物也将被表征为它们的 使用功能测定法测定可逆结合性质。(3)明确了解CB 2配体结合 通过确定几种受体-配体复合物的3-D结构来确定位点。为了实现这些目标， 几种晶体结构将被解决，以更好地了解分子识别，信号，并协助 设计新的化合物，然后可以作为下一代铅和药物的原型， 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.