A new interpretation of structure-function relationships in insulin-receptor interactions.

Arguments are presented for a unified theory of insulin binding which differs from presently accepted viewpoints: (1) Insulin receptors are bivalent with some motional freedom between binding units; (2) following ligand formation a conformational change occurs which leads to a restriction of receptor flexibility; (3) when both binding units are occupied, they can approach sufficiently closely with an antiparallel symmetry to permit dimer formation-related interaction of receptor-bound insulin molecules; (4) this event leads to enhanced dissociation (negative cooperativity) with kinetic features identical to the model of de Meyts; (5) the binding surface of insulin cannot include residues involved in dimer formation. If this is so, then the accepted receptor binding surface of insulin, which includes the residues involved in dimer formation, is incorrect. Arguments are brought suggesting that strongly conserved hydrophilic residues of the A chain may be involved.