Conformational basis of the receptor-binding potency of normal and mutant insulin molecules with relevance to the pathophysiology of noninsulin dependent diabetes mellitus (NIDDM)

Abstract

Residues 23–26 (Gly-, Phe-, Phe-, Tyr) of the B-chain of insulin constitute a critical area of the receptor-binding region of the molecule. Three chemically distinct mutant insulins have recently been identified in patients with NIDDM, each involving substitution of either B24 of B25 phenylalanine. Two of the mutations have been unambiguously characterized: a B25 phenylalanine-to-leucine substitution [B25(Phe Leu)], and the other, a B24 phenylalanine-to-serine [B24 (Phe Ser)]. We have calculated the preferred conformations of normal and mutant insulins using a global optimization method developed by us earlier. The mutant insulins exhibit significant alterations in conformation and in the average distances between amino acid side-chains as compared to normal insulin. Therefore, the decreased binding affinity of mutant insulin could be either due to an alteration in the nature of the substituted residue (hydrophilic in place of hydrophobic) or to the alteration in one or more critical side-chain distances in the case of a hydrophobic to hydrophobic substitution.