Insulin-induced conformational changes in the full-length insulin receptor: structural insights gained from molecular modeling analyses.

Insulin receptor plays an important role in the regulation of energy metabolism. Dysfunction of insulin receptor (IR) can lead to many disease states, such as diabetes mellitus. Deciphering the complex dynamic structures of human IR and its mechanism of activation would greatly aid in understanding IR-mediated signaling pathways and also in designing new drugs (including nonpeptidal insulin analogs) to treat diabetes mellitus. Experimental evidence about IR structures has been gradually obtained by biologists over the past three decades. Based on available experimental structures of IR in different states, here we employ molecular modeling approach to construct the full-length IR structures in different states and model its structural and conformational changes during insulin-induced IR activation. Several key possible intermediate states are constructed based on structural alignment, rotation, and computational modeling. Based on the structures of the full-length IR in different states, it appears that there are two possible conformational transition pathways: one is symmetric and the other one is asymmetric. Structural changes and motions of different domains of the full-length IR along the pathways are analyzed. The role of insulin binding to IR in facilitating the conformational transition of the receptor is analyzed. Information and insights derived from our present structural modeling analyses may aid in understanding the complex dynamic, structural, and conformational changes during the process of IR activation.