Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China.
iHuman Institute, ShanghaiTech University, Shanghai 201210, China.
Sci Adv. 2022 Dec 23;8(51):eadd3709. doi: 10.1126/sciadv.add3709.
The human adenosine A receptor (AR) is a class A G protein-coupled receptor that is involved in several major physiological and pathological processes throughout the body. AR recognizes its ligands adenosine and NECA with relatively low affinity, but the detailed mechanism for its ligand recognition and signaling is still elusive. Here, we present two structures determined by cryo-electron microscopy of AR bound to its agonists NECA and BAY60-6583, each coupled to an engineered G protein. The structures reveal conserved orthosteric binding pockets with subtle differences, whereas the selectivity or specificity can mainly be attributed to regions extended from the orthosteric pocket. We also found that BAY60-6583 occupies a secondary pocket, where residues V250 and N273 were two key determinants for its selectivity against AR. This study offers a better understanding of ligand selectivity for the adenosine receptor family and provides a structural template for further development of AR ligands for related diseases.
人源腺苷 A 受体（AR）是一种 A 类 G 蛋白偶联受体，参与体内多个主要的生理和病理过程。AR 以相对较低的亲和力识别其配体腺苷和 NECA，但配体识别和信号转导的详细机制仍不清楚。在这里，我们通过冷冻电镜技术确定了与激动剂 NECA 和 BAY60-6583 结合的 AR 的两种结构，每种结构都与一种工程化的 G 蛋白偶联。这些结构揭示了保守的正位结合口袋，存在细微差异，而选择性或特异性主要归因于从正位口袋延伸出来的区域。我们还发现 BAY60-6583 占据了一个次要口袋，其中 V250 和 N273 两个残基是其对 AR 选择性的关键决定因素。这项研究为腺苷受体家族的配体选择性提供了更好的理解，并为进一步开发用于相关疾病的 AR 配体提供了结构模板。
