[Chemical structure, active sites and receptor binding of insulin molecule and its signal transduction]

Biologically active insulin consists of two polypeptide chains, the A chain(21 amino acids) and the B chain(30 amino acids). Several regions of invariability closely related to the biological activity, such as (a) the position of cysteines that form the disulfide bridges, (b) the N- and C-terminal regions of the A-chain, and (c) hydrophobic residues at the C-terminus of the B chain. The functional insulin receptor is a heterotetrameric protein composed of two alpha and two beta subunits. The alpha subunits contain the insulin binding site and the binding causes conformational changes in the receptor molecule. The quaternary structure of the beta subunit then changes to allow for stimulating autophosphorylation of its tyrosine residues. Those in the catalytic domain(tyrosines 1146, 1150, 1151) are essential to promote the kinase activity of the receptor toward other protein substrates in insulin signalling system. The elucidation of detailed mechanisms of insulin binding to the receptor will be useful for the development of a novel hypoglycemic agent 'insulin receptor agonist', which directly acts on the insulin site and can be orally administered for the treatment of diabetes mellitus.