Two functionally distinct mechanisms of GCK activation. α-type activation, as exemplified by the α13-helix variant, shifts the ensemble structure toward a state resembling the glucose-bound conformation, as evidenced by increased sharpness of cross-peaks, shifting of mobile loop cross-peaks away from the disordered region of the spectrum, and the appearance of new cross-peaks. β-type activation, as exemplified by the β-hairpin variant, alters the structure and/or dynamics of the mobile loop (cyan), as evidenced by increased sharpness of mobile loop cross-peaks that remain in the disordered region of the spectrum.