Comparison of CCK-8 binding interactions with CCK1R in Gs and Gq mimetic protein complexes.
(A, B) Alignment of the 2 structures. (A) Alignment of receptor and CCK-8 peptide. The largest difference in the CCK1R was in the location of ICL2 that is further away from the receptor core in the complex with the Gq mimetic protein. (B) Alignment of the full complex illustrating differences in the engagement and orientation of the G proteins. The receptor and G proteins are displayed in ribbon format. (C) Overlay of CCK-8 and interacting CCK1R residues in the binding pocket for the Gs and Gq mimetic complexes. The CCK-8 peptide and modelled cholesterol are displayed in ball and stick representation. The CCK-8 residues are displayed in stick format, coloured by heteroatom (Gs complex, gold; Gq mimetic complex, yellow). CCK1R side chains that interact with the peptide are shown in stick format (Gs complex, light green; Gq mimetic complex, dark green). (D) Comparison of the CCK-8/CCK1R with OxB/OX2R (blue ligand, pink receptor) binding pockets. The peptides overlap in the location of the amidated carboxyl-terminal tetrapeptide but differ in conformation and position of N-terminal amino acids. CCK-8 interacts more with ECL2 than ECL3, while the reverse is true for OxB. (E) Surface electrostatic potential of the CCK1R binding pocket. CCK1R has a very positive surface charge. (F) In contrast, the OX2R binding pocket has a very negative surface potential. CCK, cholecystokinin; CCK1R, cholecystokinin type 1 receptor.
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