Structure of the Gq-coupled adhesion receptor ADGRL4

Nat Commun. 2025 Dec 30;17(1):907. doi: 10.1038/s41467-025-67629-0.

Abstract

Adhesion G protein-coupled receptors (aGPCRs) are a 32-member family of Class B GPCRs that have diverse cellular roles including mechanosensation, cell-fate determination, neurodevelopment, immune function and tumour biology. ADGRL4 is upregulated in the tumour microenvironment and is implicated in tumour pathogenesis across a broad range of malignancies. Inhibiting ADGRL4 is a potential therapeutic treatment for currently intractable cancers such as glioblastoma. Previous work suggested that ADGRL4 does not signal through G protein coupled pathways. However, using a sensitive bioluminescent assay, we demonstrate here that ADGRL4 couples weakly to the heterotrimeric G protein Gq, whilst there is no robust coupling to other G proteins (Gs, G12, Go) or β-arrestin 1 or 2. We determine the cryo-EM structure of ADGRL4 coupled to a heterotrimeric Gq complex to a resolution of 3.1 Å. The overall fold of ADGRL4 is similar to that of other aGPCRs, but the coupling to Gq is distinct with fewer interactions between the receptor and G protein. The structure is consistent with ADGRL4 being activated by its tethered agonist and represents an important step towards the development of potential inhibitors for the treatment of multiple tumour types.

MeSH terms

  • Cryoelectron Microscopy
  • GTP-Binding Protein alpha Subunits, Gq-G11* / chemistry
  • GTP-Binding Protein alpha Subunits, Gq-G11* / metabolism
  • HEK293 Cells
  • Humans
  • Protein Binding
  • Receptors, G-Protein-Coupled* / chemistry
  • Receptors, G-Protein-Coupled* / genetics
  • Receptors, G-Protein-Coupled* / metabolism
  • Receptors, G-Protein-Coupled* / ultrastructure

Substances

  • GTP-Binding Protein alpha Subunits, Gq-G11
  • Receptors, G-Protein-Coupled