(A) Overall structures of IDE dimer in the presence and absence of insulin. Models are shown as ribbons within the electron density map. O, open state; pO, partially open state; pC, partially-closed state. IDE-N and IDE-C are colored in cyan and grey, respectively; insulin inside the catalytic chamber of IDE is colored in yellow. For simplicity, Fab is not shown. (B) Comparison of four distinct conformational states within IDE structures; two pC states in the insulin-bound cryoEM IDE structure, three pO and three O states in apo-IDE cryoEM structures, and a closed structure from previous crystallographic work (Guo et al., 2010; Malito et al., 2008b2008; Manolopoulou et al., 2009; Noinaj et al., 2011; Ren et al., 2010; Shen et al., 2006). The buried surface between IDE-N and IDE-C, distance between the center of mass (COM) of IDE D1 and D4 domains, and dihedral angles (absolute values) between COM of IDE D1-D2 and COM of D3-D4 are shown below the ribbon presentation of IDE structures. (C) Structural comparison of IDE states aligned by IDE-N (top) or IDE-C (bottom), showing rigid body motion of IDE-N and IDE-C guided by the loop connecting IDE-N and IDE-C. (D) Structural basis of IDE open structure primed to capture insulin by size and charge complementarity. The boundaries for the substrate-binding catalytic chambers of IDE-N and IDE-C are marked by a dashed line. The color scale is set from −3 kT/e (red) to 3 kT/e (blue) calculated using APBS 2.1.