Adhesion G-protein coupled receptor F1
G protein-coupled receptor activity
Structural basis of adhesion GPCR GPR110 activation by stalk peptide and G-proteins coupling.
Adhesion G protein-coupled receptors (aGPCRs) are keys of many physiological events and attractive targets for various diseases. aGPCRs are also known to be capable of self-activation via an autoproteolysis process that removes the inhibitory GAIN domain on the extracellular side of receptor and releases a stalk peptide to bind and activate the transmembrane side of receptor. However, the detailed mechanism of aGPCR activation remains elusive. Here, we report the cryo-electron microscopy structures of GPR110 (ADGRF1), a member of aGPCR, in complex with G<sub>q</sub>, G<sub>s</sub>, G<sub>i</sub>, G<sub>12</sub> and G<sub>13.</sub> The structures reveal distinctive ligand engaging model and activation conformations of GPR110. The structures also unveil the rarely explored GPCR/G<sub>12</sub> and GPCR/G<sub>13</sub> engagements. A comparison of G<sub>q</sub>, G<sub>s</sub>, G<sub>i</sub>, G<sub>12</sub> and G<sub>13</sub> engagements with GPR110 reveals details of G-protein engagement, including a dividing point at the far end of the alpha helix 5 (αH5) of Gα subunit that separates G<sub>q</sub>/G<sub>s</sub> engagements from G<sub>i</sub>/G<sub>12</sub>/G<sub>13</sub> engagements. This is also where G<sub>q</sub>/G<sub>s</sub> bind the receptor through both hydrophobic and polar interaction, while G<sub>i</sub>/G<sub>12</sub>/G<sub>13</sub> engage receptor mainly through hydrophobic interaction. We further provide physiological evidence of GPR110 activation via stalk peptide. Taken together, our study fills the missing information of GPCR/G-protein engagement and provides a framework for understanding aGPCR activation and GPR110 signaling.