School of Pharmacy, Sungkyunkwan University, 2066 Seoburo, Jangan-gu, Suwon, 16419, Republic of Korea.
Arch Pharm Res. 2020 Sep;43(9):890-899. doi: 10.1007/s12272-020-01263-w. Epub 2020 Aug 14.
G protein-coupled receptors (GPCRs) belong to a major receptor family and regulate important physiological and pathological functions. Upon agonist activation, GPCRs couple to G proteins and induce the activation of G protein-dependent signaling pathways. The agonist-activated GPCRs are also phosphorylated by G protein-coupled receptor kinases (GRKs), which promote their interaction with arrestins. Arrestin binding induces desensitization (i.e., inability to couple to G proteins) and/or internalization of GPCRs. Arrestins not only desensitize and/or internalize GPCRs but also mediate other downstream signals such as mitogen-activated protein kinases. G protein-mediated signaling and arrestin-mediated signaling often result in different functional outcomes, and therefore, it has been suggested that signaling-selective regulation of GPCRs could lead to the development of more effective treatments with fewer side effects. Thus, studies have attempted to develop functionally biased (i.e., signaling-selective) GPCR-targeting drugs. To this end, it is important to elucidate the structural mechanism underlying functionally biased GPCR signaling, which includes understanding the structural mechanism underlying the GPCR-arrestin interaction. This review aims discuss the structural aspects of the GPCR-arrestin interaction, focusing on the differences between reported GPCR-arrestin complex structures.
G 蛋白偶联受体（GPCRs）属于主要的受体家族，调节重要的生理和病理功能。在激动剂激活后，GPCR 与 G 蛋白偶联，并诱导 G 蛋白依赖的信号通路的激活。激动剂激活的 GPCR 也被 G 蛋白偶联受体激酶（GRKs）磷酸化，这促进了它们与阻滞蛋白的相互作用。阻滞蛋白的结合诱导 GPCR 的脱敏（即不能与 G 蛋白偶联）和/或内化。阻滞蛋白不仅使 GPCR 脱敏和/或内化，还介导其他下游信号，如丝裂原活化蛋白激酶。G 蛋白介导的信号和阻滞蛋白介导的信号通常导致不同的功能结果，因此，有人提出 GPCR 的信号选择性调节可以导致开发出副作用更少的更有效的治疗方法。因此，研究人员试图开发具有功能偏向性（即信号选择性）的 GPCR 靶向药物。为此，阐明功能偏向性 GPCR 信号的结构机制非常重要，其中包括理解 GPCR-阻滞蛋白相互作用的结构机制。本综述旨在讨论 GPCR-阻滞蛋白相互作用的结构方面，重点介绍报道的 GPCR-阻滞蛋白复合物结构之间的差异。
