Two crystal structures of the FK506-binding domain of Plasmodium falciparum FKBP35 in complex with rapamycin at high resolution

Abstract

Antimalarial chemotherapy continues to be challenging in view of the emergence of drug resistance, especially artemisinin resistance in Southeast Asia. It is critical that we identify novel anti-malarial drugs that inhibit new targets with unexplored mechanisms of action. It has been demonstrated that the immunosuppressive drug rapamycin, currently in clinical use to prevent organ transplant rejection, has anti-malarial effects. The Plasmodium falciparum target protein is PfFKBP35, a unique immunophilin FK506 binding protein (FKBP). This protein family binds rapamycin, FK506 and other immunosuppressive and non-immunosuppressive macrolactones. Here we report two crystallographic structures of rapamycin in complex with the FK506-binding domain of PfFKBP35 at high resolution, in both its oxidised and reduced forms. Comparison to the human FKBP12- rapamycin complex reported earlier, the structures reveal structural differences in the 4-6 segment that lines the rapamycin binding site. Structural differences between the Plasmodium protein and the human hFKBP12 include the replacement of Cys-106 and Ser-109 by His-87 and Ile-90, respectively. Cys-106 which is close (4-5 Å) from atoms of rapamycin, suggests possible routes for the rational design of analogues of rapamycin with specific antiparasitic activity. Comparison of the structures with the PfFKBD-FK506 complex shows that both drugs interact with the same binding site residues. These two new structures highlight the structural differences and the specific interactions that must be kept in consideration for the rational design of rapamycin analogues with anti-malarial activity that specifically bind to PfFKBP35 without immunosuppressive effect