Novel Druggable Sites of Insulin-Degrading Enzyme Identified through Applied Structural Bioinformatics Analysis

Abstract

Insulin-degrading enzyme (IDE) plays critical roles in proteolysis of diverse substrates, like insulin and amyloid β. Pathologically, IDE is implicated in type 2 diabetes mellitus and Alzheimer's diseases, but potent and selective regulators of IDE remain elusive. We have applied structural bioinformatics techniques to the largest ensemble of IDE structures determined hitherto, identified structural clusters associated with distinct conformational states and their respective clustroids. IDE utilizes its intrinsic large-scale structural motions to adopt multiple conformational states and perform molecular functions. The conformational space occupied by IDE structures can be shifted through mutations and inter-molecular interactions with other proteins, small molecules or substrate peptides. We observed that IDE-N is generally more dynamic than IDE-C and suggested that there are possibly other open conformational states of IDE whose structures remain unknown. We also identified novel druggable sites that are specific to particular conformational states of IDE, these sites can potentially be explored for designing investigative probes or therapeutic agents for specific spatiotemporal contexts.