a, MRGPRX2 and MRGPRX4 have a unique structural arrangement at the PIF motif compared to the G protein coupled active structures of 5-HT2AR (PDB ID 6WHA), A2AR (PDB ID 5G53) and β2AR (PDB ID 3SN6). Residue 5.50 shifts away from the TM3-TM6 interface and does not engage L3.40 and F6.44 in MRGPRX2 and MRGPRX4. b, With G6.48, TM6 of both MRGPRX2 and MRGPRX4 packs closer to TM3 compared to the G protein coupled active structures of 5-HT2AR (PDB ID 6WHA), A2AR (PDB ID 5G53) and β2AR (PDB ID 3SN6), leading to an occluded canonical agonist binding pocket. c, (R)-ZINC-3573, cortistatin-14 and MS47134 bind to MRGPRX2 and MRGPRX4 at a position that is far away from residue 6.48, respectively. Cortistatin-14 is shown as cartoon. Small molecule compounds of receptors are shown as spheres.