Structural insights into Plasmodium PPIases

Abstract

Malaria is one of the most prevalent infectious diseases posing a serious challenge over the years, mainly owing to the emergence of drug-resistant strains, sparking a need to explore and identify novel protein targets. It is a well-known practice to adopt a chemo-genomics approach towards identifying targets for known drugs, which can unravel a novel mechanism of action to aid in better drug targeting proficiency. Immunosuppressive drugs cyclosporin A, FK506 and rapamycin, were demonstrated to inhibit the growth of the malarial parasite, Plasmodium falciparum. Peptidyl prolyl cis/trans isomerases (PPIases), comprising cylcophilins and FK506-binding proteins (FKBPs), the specific target of these drugs, were identified in the Plasmodium parasite and proposed as an antimalarial drug target. We previously attempted to decipher the structure of these proteins and target them with non-immunosuppressive drugs, predominantly on FKBP35. This review summarizes the structural insights on Plasmodium PPIases, their inhibitor complexes and perspectives on drug discovery.

Keywords: FK506; FKBP; PPIase; cyclophilin; cyclosporin; malaria; plasmodium.

Figure 1

Structure and comparison of Plasmodium FKBPs. (A) The cartoon representation of PfFKBD35 in complex with FK506 (in ball and stick mode). The β0 observed here is not present in hsFKBPs. Similarly, the two unique residues pertaining to Plasmodium FKBP35’s Cys106 and Ser109 in the β5-β6 loop are shown in stick mode. (B) The overlay of FK506 (salmon), rapamycin (pale blue) and D44 (green) bound structures of PfFKBD35, with the nearest atom from Cys106 and Ser109 shown in broken lines. (C) Similarly, the overlay of FK506 (salmon), substrate-ALPF (pale blue), D44 (green) and SRA (orange) bound structures of PvFKBD35. (D) The nearest distance between the ligands and the unique Cys and Ser residues are listed for comparison, indicating the D44 is oriented closer to these residues.