Constitutive arrestin recruitment by orphan GPR52 via an atypical binding mode

Dear Editor,

Arrestins and G proteins are integral to G protein-coupled receptor (GPCR) signal transduction, typically recruited following receptor activation by a ligand. Understanding the modes of interactions for arrestins provides insights into the complexity and versatility of cellular responses mediated by GPCRs. To date, only a few structures of agonist-activated GPCR–β-arrestin1 (βarr1) complexes have been resolved by cryo-electron microscopy (cryo-EM).^1,2 Interestingly, most of the reported GPCR–βarr1 complexes primarily exhibit core engagement conformations for βarr1, although an unstable ‘hanging’ conformation has also been observed for M2R–βarr1.³ In contrast, the class B GCGR–βarr1 complex exhibits a tail engagement mode.² It remains unclear whether the core conformation is a characteristic of class A receptors in engaging βarr1.