Figure 4. Models of the Structures of ApoE3 and ApoE4.
(A) ApoE4 displays a unique property called domain interaction caused by the ionic interaction between arginine-61 in the N-terminal domain with glutamic acid–255 in the C-terminal domain. ApoE3 is significantly less likely to undergo domain interaction than apoE4.
(B) ApoE4 domain interaction can be blocked by a small-molecule apoE4 structure corrector that disrupts the ionic interaction between arginine-61 and glutamic acid–255. This converts apoE4 to an apoE3-like molecule both structurally and functionally (Huang, 2010; Mahley and Rall, 2000; Mahley et al., 2006, 2009). ApoE4SC, apoE4 structure corrector. Figure reprinted with permission from Mahley and Huang, Small-molecule structure correctors target abnormal protein structure and function: The structure corrector rescue of apolipoprotein E4–associated neuropathology. J. Med. Chem. 55: 8997–9008, 2012. Copyright 2012 American Chemical Society.