孤儿受体的结构研究与配体发现

孤儿受体（orphan receptors）是指还未发现内源性配体且功能有待发掘的一类G蛋白偶联受体（GPCRs），已报道的有100多个成员。近年来关于孤儿受体的功能报道引起了广泛关注，其中不乏一些潜在的疾病和药物靶点，如与神经性疾病相关的GPR52，与糖尿病和肥胖相关的GPR21，以及与多种癌症相关的GPR68等。对于这类受体的结构研究，不仅是探索其生物学功能的基础，同时也为工具配体的设计，以及内源性配体的发现（即“脱孤”）提供重要的线索。该项目中，申请人课题组将对上述几个典型孤儿受体展开结构与功能研究，通过晶体学、冷冻电镜以及生化与细胞功能实验等方法探索受体的作用机理以及配体结合模式并加以验证。目前已取得重要的前期研究基础，成功解析了首个孤儿受体GPR52的多种状态的晶体和冷冻电镜结构，揭示了孤儿受体重要的生物学基础，为后续研究的开展提供了经验与思路。

G-protein coupled receptors (GPCRs) constitute the largest membrane protein family in the human genome with over 800 members identified so far. These receptors are associated with a variety of physiological and pathological processes and are hence targets for over 30% of modern drugs. The molecular recognition of ligand in the receptor—the ligand binding mode and the receptor’s conformational changes upon ligand binding are considered crucial for understanding the mechanism of signal transduction. Orphan GPCRs, whose endogenous ligands are yet to be identified, occupy a substantial population with over 100 members. Recent studies reported important functions of some orphan GPCRs, shedding light on their promising drug target opportunities. Among them, three receptors caught our special interests: GPR52—an emerging target for a variety of psychiatric diseases given its important roles in the brain; GPR21—a close homolog to GPR52 which serves as potential target for type2 diabetes and obesity owing to its signaling function; GPR68—a proton-sensing receptor that is recently considered target for various cancers attributed to its wide tissue distribution and unique function to modulate acidic condition in the tumor environment. In this project, we aim to solve 3D structures of these receptors in the absence or presence of tool ligand and/or cognate G proteins by x-ray crystallography and single particle cryo-EM. Our recent progress including the disclosure of the full structural landscape of GPR52 is the first breakthrough in this field. We will continue investigating the structures of GPR52 and the other two orphan receptors and provide insight to their biological functions and more importantly, their ligand discovery toward deorphanization.