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At the residue level, signaling initiation by either peptide 20, tirzepatide or endogenous peptide hormones rendered a common arrangement of residue contacts for the three receptors, including the reorganization of the central polar network that located just below the peptide binding site, opening of the hydrophobic packing to favor the formation of the TM6 kink at the PXXG motif and the rearrangement of two polar networks (HETX motif and TM2-6-7-helix 8) at the cytoplasmic face 33,34