Comparison of activation motifs between CCK1-active (green) and OX₂R-active (pink) and inactive (grey).

(A) CWxP motif. While there is no direct interaction between CCK-8 and W326^6.48 of the CWxP motif, residue F8^CCK interacts with F330^6.52, which, in turn, interacts with W326^6.48. Of note, residue 6.48 is not conserved in OX₂R, and there is no movement between the inactive and active states at this position. Given the absence of an inactive CCK1R structure the role of the CWxP motif in CCK1R is unclear. Nevertheless, the position of W326^6.48 stabilises the outward rotation of F322^6.44 within the PI(T)F motif. (B) Comparison of the PI(T)F motif shows this activation motif is largely conserved between CCK1R and OX2R. Upon activation, there is a modest movement of F^6.44 for OX₂R. CCK1R is even further shifted away from T129^3.40 and P221^5.50. (C) NPxxY motif. Upon activation, there is a clear rotation of Y^7.53 for OX₂R. CCK1R Y370^7.53 overlays with the active form of OX₂R and forms a water mediated interaction Y229^5.58. (D) E/DRY motif. In the OX₂R, inactive state R^3.50 forms a salt-bridge with E^3.49; these residues are conserved in CCK1R. Upon activation, R^3.50 rotates up and inwards to form a hydrogen bond with Y^5.58, the position of these residues overlay with the active CCK1R. CCK, cholecystokinin; CCK1R, cholecystokinin type 1 receptor.

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