Exploring insulin-receptor dynamics: Stability and binding mechanisms

Insulin binding to the insulin receptor (IR) induces large conformational changes leading to receptor activation. Although there exists a considerable number of IR structures in different conformational and insulin-saturation states, they cannot provide dynamic information or the resolved order of events leading to receptor activation. In this study, we employed molecular dynamics (MD) simulations to the experimentally solved structures of IR-insulin complexes occurring under physiological concentration conditions. We observed that insulin bound to the hybrid sites induced opening of site 1, and that site 1-bound insulin contributed to the extension of the α helix in the C terminus of the α chain (αCT) and increased inter-domain stabilization. Many models have previously been proposed for the activation of IR. Based on our observations, we propose a novel “ladder-climbing” mechanism of insulin-induced IR activation, where insulin gradually migrates from site 2 to site 1 while inducing a controlled conformational change in IR.