Structure of the G_q-coupled adhesion receptor ADGRL4, a GPCR implicated in cancer

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 G_q, whilst there was no robust coupling to other G proteins (G_s, G₁₂, G_o) or β-arrestin 1 or 2. We determined the cryo-EM structure of ADGRL4 coupled to a heterotrimeric G_q complex to a resolution of 3.1 Å. The overall fold of ADGRL4 is similar to that of other aGPCRs, but the coupling to G_q 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.