Add time:09/04/2019         Source:sciencedirect.com

The hydrophobic core of vertebrate insulins contains an invariant isoleucine residue at position A2. Lack of variation may reflect this side-chain’s dual contribution to structure and function: IleA2 is proposed both to stabilize the A1-A8 α-helix and to contribute to a “hidden” functional surface exposed on receptor binding. Substitution of IleA2 by alanine results in segmental unfolding of the A1-A8 α-helix, lower thermodynamic stability and impaired receptor binding. Such a spectrum of perturbations, although of biophysical interest, confounds interpretation of structure-activity relationships. To investigate the specific contribution of IleA2 to insulin’s functional surface, we have employed non-standard mutagenesis: inversion of side-chain chirality in engineered monomer allo-IleA2-DKP-insulin. Although the analogue retains native structure and stability, its affinity for the insulin receptor is impaired by 50-fold. Thus, whereas insulin’s core readily accommodates allo-isoleucine at A2, its activity is exquisitely sensitive to chiral inversion. We propose that the IleA2 side-chain inserts within a chiral pocket of the receptor as part of insulin’s hidden functional surface.

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