Fig. 3: General activation mechanisms of class A and B GPCRs bound to peptide ligands.

a A schematic representation of the inactive and active states of class A GPCRs. While small-molecule antagonists typically bind into the transmembrane (TM) pocket stabilizing the receptor in an inactive state, peptide agonists, generally, interact with ECL2 and the N-tail, which are flexible in the absence of a peptide ligand (indicated by a dashed black arrow), as well as with the TM pocket. Agonist binding induces conformational changes in the TMD, resulting in the outward movement of the cytoplasmic segments of TM5 and TM6 (indicated by a red arrow), thereby facilitating G protein binding. b A schematic representation of the inactive and active states of class B GPCRs. These receptors possess a large N-terminal ECD, which is flexible in the absence of a peptide ligand (dashed black arrow). Peptide agonists engage both the ECD and TMD. In the active state, a sharp kink or bend in the PxxG motif of TM6 promotes the outward movement of its cytoplasmic segment (red arrow), creating an open cavity for G protein binding.