Insulin

Abstract

The protein hormone insulin, produced in the pancreas and stored in granules, interacts, after secretion into the blood stream, with the extracellular domain of the insulin receptor. This interaction initializes a signal transduction cascade that ultimately results in glucose absorption and metabolism. In the presence of zinc ion, insulin crystallizes as a threefold symmetric T 6 hexamer complexed to two zinc ions. When phenol, m ‐cresol, or resorcinol is present in the crystallizing media, the first eight residues of all B‐chains undergo a conformational change from extended to α‐helical producing an R 6 hexamer. In the presence of thiocyanate or chloride ion, only residues 4 through 8 in the B‐chains of one trimer undergo the conformational change to produce a T 3 R 3 f hexamer. This allosteric behavior of the insulin hexamer has been observed in the solid state as well as in solution. Like the T 6 hexamer, each zinc ion that lies on the crystallographic threefold axis is octahedrally coordinated by NE2s of three symmetry related HisB10 residues and three water molecules. Because of the conformational transition from T to either R or R f , there is not sufficient space in an R‐ or R f ‐state trimer to accommodate octahedral coordination, and, therefore, zinc adopts tetrahedral coordination through bonds to the three symmetry related HisB10 NE2 atoms and either to a water molecule or to a chloride ion. In the case of T 3 R 3 f hexamers, three additional zinc binding sites exist between symmetry related R f ‐state monomers in which each zinc ion is coordinated by NE2 of a second orientation of the side chain of HisB10, NE2 of HisB5 of an adjacent monomer, and two chloride ions. From a total of 34 crystal structures of hexameric insulin, mean ZnNE2 bond distances of 2.00 or 2.10 Å are observed in tetrahedral or octahedral geometry, respectively.