Structural basis of tethered agonism of the adhesion GPCRs ADGRD1 and ADGRF1.

Adhesion G protein-coupled receptors (aGPCRs) are essential for a variety of physiological processes such as immune responses, organ development, cellular communication, proliferation and homeostasis1-7. An intrinsic manner of activation that involves a tethered agonist in the N-terminal region of the receptor has been proposed for the aGPCRs8,9, but its molecular mechanism remains elusive. Here we report the G protein-bound structures of ADGRD1 and ADGRF1, which exhibit many unique features with regard to the tethered agonism. The stalk region that proceeds the first transmembrane helix acts as the tethered agonist by forming extensive interactions with the transmembrane domain; these interactions are mostly conserved in ADGRD1 and ADGRF1, suggesting that a common stalk-transmembrane domain interaction pattern is shared by members of the aGPCR family. A similar stalk binding mode is observed in the structure of autoproteolysis-deficient ADGRF1, supporting a cleavage-independent manner of receptor activation. The stalk-induced activation is facilitated by a cascade of inter-helix interaction cores that are conserved in positions but show sequence variability in these two aGPCRs. Furthermore, the intracellular region of ADGRF1 contains a specific lipid-binding site, which proves to be functionally important and may serve as the recognition site for the previously discovered endogenous ADGRF1 ligand synaptamide. These findings highlight the diversity and complexity of the signal transduction mechanisms of the aGPCRs.

GPR91, a critical signaling mechanism in modulating pathophysiologic processes in chronic illnesses.

Succinate receptor GPR91 is one of G protein-coupled receptors (GPCRs), and is expressed in a variety of cell types and tissues. Succinate is its natural ligand, and its activation represents that an intrinsic metabolic intermediate exerts a regulatory role on many critical life processes involving pathophysiologic mechanisms, such as innate immunity, inflammation, tissue repair, and oncogenesis. With the illustration of 3-dimensional crystal structure of the receptor and discovery of its antagonists, it is possible to dissect the succinate-GPR91-G protein signaling pathways in different cell types under pathophysiological conditions. Deep understanding of the GPR91-ligand binding mode with various agonists and antagonists would aid in elucidating the molecular basis of a spectrum of chronic illnesses, such as hypertension, diabetes, and their renal and retina complications, metabolic-associated fatty liver diseases, such as nonalcoholic steatohepatitis and its fibrotic progression, inflammatory bowel diseases (Crohn's disease and ulcerative colitis), age-related macular degeneration, rheumatoid arthritis, and progressive behaviors of malignancies. With better delineation of critical regulatory role of the succinate-GPR91 axis in these illnesses, therapeutic intervention may be developed by specifically targeting this signaling pathway with small molecular antagonists or other strategies.