马年新年第一天！浙江大学发表最新Nature论文：从头设计GPCR外骨骼蛋白，靶向调控GPCR跨膜结构域

Core Viewpoint - The article discusses a groundbreaking study on GPCR (G-protein-coupled receptor) modulation through the introduction of a novel concept called "GPCR Exoframe Modulators" (GEM), which utilizes deep learning for the design of proteins that target GPCR transmembrane domains, offering new therapeutic avenues for GPCR-related diseases [2][3][4]. Group 1 - GPCR is the largest membrane protein family in the human body, responsible for transducing various extracellular signals and regulating a wide range of physiological processes, making it a primary drug target [2]. - The research team from Zhejiang University published their findings in Nature, introducing the concept of GEM, which can specifically bind to the transmembrane surface of GPCRs and stabilize specific receptor conformations [3][4]. - The study highlights the potential of deep learning methods in designing function-oriented membrane proteins, marking a significant advancement in GPCR allosteric modulation [8]. Group 2 - The research focused on the dopamine D1 receptor (D1R) as a prototype model, investigating four types of GEM: GEM anchor, GEM BAM, GEM NAM, and GEM ago-PAM, which exhibit various allosteric modulation functions [6]. - Among these, GEM ago-PAM has shown the ability to restore the activity of multiple D1R loss-of-function mutants, providing a new potential target for the treatment of GPCR-related diseases [6][8]. - The study emphasizes that targeting transmembrane domains with GEM can serve as an effective tool for GPCR allosteric modulation, showcasing the innovative approach to drug design [8].