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. 2015 Mar 11;290(18):11246–11257. doi: 10.1074/jbc.M114.605410

FIGURE 7.

FIGURE 7.

Compartmentalized accumulation of cAMP and MRP4-CFTR-containing macromolecular complexes contributes to drug-induced diarrhea. A, molecular interaction of irinotecan with MRP4. Irinotecan docked to MRP4 as expected, forming one hydrogen bond with the Arg-998 residue of 2.2 Å, and the conformation shows a docking score of −10.975 Kcal/mol (upper panel). Left and right panels, far (left panel) and close-up (right panel) views of docking poses of irinotecan in MRP4 (lower panel). The yellow-dotted line in the circle represents a hydrogen bond between irinotecan and MRP4. Sticks are colored according to atom type: carbon (gray), hydrogen (dark gray), oxygen (red), and nitrogen (blue). B, pictorial representation of a mechanism underlying the irinotecan-induced intestinal fluid secretion (and thus secretory diarrhea) through MRP4-coupled and CFTR-mediated protein-protein interactions. Binding of irinotecan to MRP4 changes MRP4 conformation into a closed pocket and exposes the PDZ motif of MRP4, impairing cAMP efflux across the plasma membrane and enhancing the formation of MRP4-CFTR-containing macromolecular complexes, which accumulates compartmentalized cAMP in proximity to CFTR and hyper-activates its channel function and ultimately causes secretory diarrhea.