CDB25:0003700 GPR15LG — GPR15

ABSTRACT: LETTER: Dear Editor, The atypical chemoattractant receptor GPR15, a class-A GPCR, is significantly involved in colorectal cancer pathogenesis and the maintenance of intestinal immune homeostasis. Originally identified as a co-receptor for human immunodeficiency virus (HIV) or simian immunodeficiency virus (SIV), GPR15 regulates the targeted homing of T cells, notably FOXP3+ regulatory T cells (Tregs), to the lamina propria of the large intestine1. Moreover, GPR15 mediates Tregs homing and immunosuppression in the mouse colon2. Recently, a natural ligand for GPR15, C10orf99 (GPR15L), has been identified. It is a chemokine-like peptide strongly expressed in gastrointestinal tissues, confirming that the GPR15-GPR15L axis constitutes a novel signaling pathway capable of regulating intestinal homeostasis and inflammation through the migration of immune cells3,4. GPR15L shares certain characteristics with the CC chemokine family. Its uniqueness lies in the C-terminal region, serving as the activation domain, distinguishing it from traditional chemokines4. Specifically, the 11 amino acids at the C-terminus of GPR15L (GPR15LC11) have been shown to exhibit potent efficacy in activating GPR155. GPR15L shares certain characteristics with the CC chemokine family. Its uniqueness lies in the C-terminal region, serving as the activation domain, distinguishing it from traditional chemokines4. Specifically, the 11 amino acids at the C-terminus of GPR15L (GPR15LC11) have been shown to exhibit potent efficacy in activating GPR155. Understanding the molecular recognition between the GPR15L–GPR15 pair and the signaling mechanism of GPR15 via its downstream Gi proteins is crucial to providing insight into the development of peptide-derived ligands and pharmaceuticals to treat intestinal disorders. To this end, we present the Cryo-EM structure of the GPR15–Gi complex bound to GPR15LC11 at 2.9 Å resolution (Fig. 1a, b; Supplementary Figs. S1, S2, S3, Table S1 and Materials and Methods). This structural elucidation marks a significant stride towards unraveling the intricacies of GPR15-mediated signaling and provides a solid foundation for designing and optimizing therapeutic interventions targeting this pathway.