The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
University of Chinese Academy of Sciences, 100049, Beijing, China.
Nat Commun. 2020 Aug 17;11(1):4121. doi: 10.1038/s41467-020-17933-8.
Vasoactive intestinal polypeptide receptor (VIP1R) is a widely expressed class B G protein-coupled receptor and a drug target for the treatment of neuronal, metabolic, and inflammatory diseases. However, our understanding of its mechanism of action and the potential of drug discovery targeting this receptor is limited by the lack of structural information of VIP1R. Here we report a cryo-electron microscopy structure of human VIP1R bound to PACAP27 and Gs heterotrimer, whose complex assembly is stabilized by a NanoBiT tethering strategy. Comparison with other class B GPCR structures reveals that PACAP27 engages VIP1R with its N-terminus inserting into the ligand binding pocket at the transmembrane bundle of the receptor, which subsequently couples to the G protein in a receptor-specific manner. This structure has provided insights into the molecular basis of PACAP27 binding and VIP receptor activation. The methodology of the NanoBiT tethering may help to provide structural information of unstable complexes.
血管活性肠肽受体 (VIP1R) 是一种广泛表达的 B 类 G 蛋白偶联受体，也是治疗神经元、代谢和炎症性疾病的药物靶点。然而，由于缺乏 VIP1R 的结构信息，我们对其作用机制和药物发现靶点的潜力的了解是有限的。在这里，我们报告了与 PACAP27 和 Gs 三聚体结合的人 VIP1R 的冷冻电镜结构，其复合物组装通过 NanoBiT 连接策略稳定。与其他 B 类 GPCR 结构的比较表明，PACAP27 通过其 N 端插入受体跨膜束中的配体结合口袋与 VIP1R 结合，随后以受体特异性的方式与 G 蛋白偶联。该结构为 PACAP27 结合和 VIP 受体激活的分子基础提供了深入了解。NanoBiT 连接的方法学可能有助于提供不稳定复合物的结构信息。
