A STRUCTURAL SWITCH IN A MUTANT INSULIN EXPOSES KEY RESIDUES FOR RECEPTOR-BINDING

Despite years of effort to clarify the structural basis of insulin rec eptor binding no clear consensus has emerged. It is generally believed that insulin receptor binding is accompanied by some degree of confor mational change in the carboxy-terminal of the insulin B-chain. In par ticular, while most substitutions for PheB24 lead to inactive species, glycine or D-amino acids are well tolerated in this position. Here we assess the conformation change by solving the solution structure of t he biologically active (GluB16, GlyB24, desB30)-insulin mutant. The st ructure in aqueous solution at pH 8 reveals a subtle, albeit well-defi ned rearrangement of the C-terminal decapeptide involving a perturbati on of the B20-23 turn, which allows the PheB25 residue to occupy the p osition normally taken up by PheB24 in native insulin. The new protein surface exposed rationalizes the receptor binding properties of a ser ies of insulin analogs. We suggest that the structural switch is force d by the structure of the underlying core of species invariant residue s and that an analogous rearrangement of the C-terminal of the B-chain occurs in native insulin on binding to its receptor. (C) 1998 Academi c Press Limited.