Fig. 7: Schematic overview of proposed state-dependent secretin receptor dynamics.

A At the WT SecR, recruitment of G protein (green) to the dimer (protomer 1, blue; protomer 2, purple) leads to increased dynamics of the receptor ECD relative to the core, and in ECL3 with partial disengagement of the peptide N-terminus from the receptor core, which remains proximal to ECL3, promoting faster G protein activation and release. B In the absence of the dimer, the monomeric SecR (pink) forms more stable interactions with the secretin peptide N-terminus, which remains proximal to both ECL2 and ECL3, leading to slower disengagement of the peptide following G protein coupling and a slower rate of activation and release. The secretin peptide is shown in yellow. The inset panels show the predicted higher frequency engagement of the agonist with ECL3 in one of the protomers in the dimeric state, based on cysteine-trapping experiments. In the monomer, the agonist remain proximal to both ECL2 and ECL3 for longer. The structures are artificial representations only, based on Alphafold2 predictions of the inactive secretin receptor, derived from the GPCRdb³⁴, as well as the published active structure (PDB: 6WZG). Inactive, dimer and agonist-bound models underwent geometry minimization and simple dynamics in Phenix version 1.20^35,36. Structure displays were prepared using ChimeraX version 1.6.1³⁷.