Calcineurin inhibitors structure

Calcineurin inhibitor nephrotoxicity presents as two distinct forms of renal injury. Acute nephrotoxicity is a dose-dependent, hemodynamically mediated disorder, not accompanied by particular or permanent structural changes which is reversible with decrease or discontinuation of the offending drug. On the other hand, calcineurin inhibitor-induced chronic nephrotoxicity is an insidious lesion, characterized by an irreversible and progressive renal interstitial fibrosis, which may cause important impairment in renal function and even stage 5 chronic kidney disease. 

Perhaps the most effective immunosuppressive drugs in routine use are the calcineurin inhibitors, cyclosporine and tacrolimus, which target intracellular signaling pathways induced as a consequence of T-ceU-receptor activation. Although they are structurally unrelated and bind to distinct molecular targets, they inhibit normal T-ceU signal transduction essentially by the same mechanism (see Figure 52-1). 

Figure 16 (a) The structure of calcmeurin with suhunit A in cyan. The catalytic site containing a Zn-Fe hinding site is in dark red. Subunit B in orange contains four calciimi (green) ions hound to the EF-hand motifs. Both N- and C-terminal domains of calcineurin B interact to the same extended a-helix of calcineurin A. (h) The inhibitor complex cyclosporin A (red) and cyclophilin (violet) interacts with both calcineurin subunits and blocks the catal)dic site of calcineurin ... 

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