[A2-Norleucine]insulin. An analog with unanticipated biological properties.

The simple replacement of the A2-isoleucine by norleucine in the insulin molecule gave an analog [A2-norleucine]insulin ([Nle A2]-insulin) which was found to possess insignificant receptor-binding affinity and in vitro biological activity, 0.6 and 0.9 percent, respectively, compared to the natural hormone. Circular dichroic studies showed that this analog is monomeric and indicated that the helical segment A2-A8 and the beta strand B24-B29 have undergone conformational changes. The reduced receptor-binding affinity of [Nle A2]insulin is attributed to the distortion of the A2-A8 helical segment which in turn may lead to the displacement of the A1, A5 and A19 residues which are putatively involved in receptor binding.