Kushnir Jamie, Gumpper Ryan H
Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599-7365, United States.
Biochemistry. 2025 Feb 18;64(4):749-759. doi: 10.1021/acs.biochem.4c00734. Epub 2025 Feb 3.
G-protein-coupled receptors (GPCRs) transmit an extracellular chemical/biological signal across the cell membrane, stimulating an array of intracellular signaling cascades. Canonically, these extracellular signaling molecules bind to the endogenous ligand pocket (orthosteric pocket), which stabilizes either an active or inactive conformational ensemble of the receptor. However, recent structural evidence indicates that small molecules can mediate the protein-protein interactions between the GPCR and their intracellular transducers. These small molecules are reminiscent of molecular glues and can be powerful tools for modulating GPCR signaling bias. In this Perspective, we will investigate the current structural information available on molecular glues and how they modulate GPCR signaling bias. We also examine the prospects of molecular glues and GPCR drug/probe design.
G蛋白偶联受体（GPCRs）可将细胞外化学/生物信号传递穿过细胞膜，刺激一系列细胞内信号级联反应。传统上，这些细胞外信号分子与内源性配体口袋（正构口袋）结合，该口袋可稳定受体的活性或非活性构象集合。然而，最近的结构证据表明，小分子可介导GPCR与其细胞内转导蛋白之间的蛋白质-蛋白质相互作用。这些小分子类似于分子胶水，可能成为调节GPCR信号偏向性的有力工具。在这篇观点文章中，我们将研究目前有关分子胶水的结构信息以及它们如何调节GPCR信号偏向性。我们还将探讨分子胶水以及GPCR药物/探针设计的前景。
